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a653a468061f8ed83dd4c13748824d14875bc8cb	wikidoc	Antiemetic	Antiemetic An anti-emetic is a drug that is effective against vomiting and nausea. Anti-emetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics and chemotherapy directed against cancer. # Types of Anti-emetics Anti-emetics include: - 5-HT3 receptor antagonists - these block serotonin receptors in the central nervous system and gastrointestinal tract. As such, they can be used to treat post-operative and cytotoxic drug nausea & vomiting. Dolasetron Granisetron Ondansetron Tropisetron Palonosetron (Aloxi, a new 5HT3 antagonist) - Dolasetron - Granisetron - Ondansetron - Tropisetron - Palonosetron (Aloxi, a new 5HT3 antagonist) - Dopamine antagonists act in the brain and are used to treat nausea and vomiting associated with neoplastic disease, radiation sickness, opioids, cytotoxic drugs and general anaesthetics. Domperidone Droperidol, Haloperidol, Chlorpromazine, Promethazine, Prochlorperazine. Some of these drugs are limited in their usefullness by their extra-pyramidal and sedative side-effects. Metoclopramide also acts on the GI tract as a pro-kinetic, and is thus useful in gastrointestinal disease; however, it is poor in cytotoxic or post-op vomiting. Alizapride - Domperidone - Droperidol, Haloperidol, Chlorpromazine, Promethazine, Prochlorperazine. Some of these drugs are limited in their usefullness by their extra-pyramidal and sedative side-effects. - Metoclopramide also acts on the GI tract as a pro-kinetic, and is thus useful in gastrointestinal disease; however, it is poor in cytotoxic or post-op vomiting. - Alizapride - Antihistamines (H1 histamine receptor antagonists), effective in many conditions, including motion sickness and severe morning sickness in pregnancy. Cyclizine Diphenhydramine Dimenhydrinate Meclizine Promethazine (Pentazine, Phenergan, Promacot) Hydroxyzine - Cyclizine - Diphenhydramine - Dimenhydrinate - Meclizine - Promethazine (Pentazine, Phenergan, Promacot) - Hydroxyzine - Cannabinoids are used in patients with cachexia, cytotoxic nausea & vomiting or are unresponsive to other agents. Cannabis (Marijuana). Most patients prefer smoked or vaporized cannabis over pharmaceutical versions because they do not contain all 66 cannabinoids that are in cannabis, many of which have medicinal applications. CBD is a main cannabinoid not in Marinol or Cesamet. Dronabinol (Marinol). Ninety percent of sales are for cancer and AIDS patients. The other 10% of its sales thought to be for pain, Multiple Sclerosis and also for Alzheimer's disease. Nabilone (Cesamet). Put back on the market in late 2006. A Schedule II substance unlike Marinol which is Schedule III and cannabis which is Schedule I. Sativex is an oral spray containing THC and CBD. It is currently legal in Canada and a few countries in Europe but not in the U.S. yet. - Cannabis (Marijuana). Most patients prefer smoked or vaporized cannabis over pharmaceutical versions because they do not contain all 66 cannabinoids that are in cannabis, many of which have medicinal applications. CBD is a main cannabinoid not in Marinol or Cesamet. - Dronabinol (Marinol). Ninety percent of sales are for cancer and AIDS patients. The other 10% of its sales thought to be for pain, Multiple Sclerosis and also for Alzheimer's disease. - Nabilone (Cesamet). Put back on the market in late 2006. A Schedule II substance unlike Marinol which is Schedule III and cannabis which is Schedule I. - Sativex is an oral spray containing THC and CBD. It is currently legal in Canada and a few countries in Europe but not in the U.S. yet. - Benzodiazepines Midazolam given at the onset of anaesthesia has been shown in recent trials to be as effective as ondansetron, a 5HT3 antagonist in the prevention of post-operative nausea and vomiting. Further studies need to be undertaken. Lorazepam said to be very good as an adjunct treatment for nausea along with first line medications such as Compazine or Zofran. - Midazolam given at the onset of anaesthesia has been shown in recent trials to be as effective as ondansetron, a 5HT3 antagonist in the prevention of post-operative nausea and vomiting. Further studies need to be undertaken. - Lorazepam said to be very good as an adjunct treatment for nausea along with first line medications such as Compazine or Zofran. - Anticholinergics Hyoscine (also known as Scopolamine) - Hyoscine (also known as Scopolamine) - Steroids Dexamethasone given in low dose at the onset of a general anaesthetic for surgery is an effective anti-emetic. The specific mechanism of action is not fully understood. - Dexamethasone given in low dose at the onset of a general anaesthetic for surgery is an effective anti-emetic. The specific mechanism of action is not fully understood. - Other Trimethobenzamide; thought to work on the CTZ Ginger Emetrol also claimed to be an effective anti-emetic. Propofol given intravenously. It has been used in an acute care setting in hospital as a rescue therapy for emesis. Peppermint claimed to help nausea or stomach pain when added into a tea or peppermint candies. Muscimol purported as such - Trimethobenzamide; thought to work on the CTZ - Ginger - Emetrol also claimed to be an effective anti-emetic. - Propofol given intravenously. It has been used in an acute care setting in hospital as a rescue therapy for emesis. - Peppermint claimed to help nausea or stomach pain when added into a tea or peppermint candies. - Muscimol purported as such - Non-pharmaceutical therapies with some evidence of efficacy include acupuncture and hypnosis. All drugs have potential side effects. It is important to try to reduce the baseline risk of nausea and vomiting, particularly with respect to surgery.	Antiemetic Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] An anti-emetic is a drug that is effective against vomiting and nausea. Anti-emetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics and chemotherapy directed against cancer. # Types of Anti-emetics Anti-emetics include: - 5-HT3 receptor antagonists - these block serotonin receptors in the central nervous system and gastrointestinal tract. As such, they can be used to treat post-operative and cytotoxic drug nausea & vomiting. Dolasetron Granisetron Ondansetron Tropisetron Palonosetron (Aloxi, a new 5HT3 antagonist) - Dolasetron - Granisetron - Ondansetron - Tropisetron - Palonosetron (Aloxi, a new 5HT3 antagonist) - Dopamine antagonists act in the brain and are used to treat nausea and vomiting associated with neoplastic disease, radiation sickness, opioids, cytotoxic drugs and general anaesthetics. Domperidone Droperidol, Haloperidol, Chlorpromazine, Promethazine, Prochlorperazine. Some of these drugs are limited in their usefullness by their extra-pyramidal and sedative side-effects. Metoclopramide also acts on the GI tract as a pro-kinetic, and is thus useful in gastrointestinal disease; however, it is poor in cytotoxic or post-op vomiting. Alizapride - Domperidone - Droperidol, Haloperidol, Chlorpromazine, Promethazine, Prochlorperazine. Some of these drugs are limited in their usefullness by their extra-pyramidal and sedative side-effects. - Metoclopramide also acts on the GI tract as a pro-kinetic, and is thus useful in gastrointestinal disease; however, it is poor in cytotoxic or post-op vomiting. - Alizapride - Antihistamines (H1 histamine receptor antagonists), effective in many conditions, including motion sickness and severe morning sickness in pregnancy. Cyclizine Diphenhydramine Dimenhydrinate Meclizine Promethazine (Pentazine, Phenergan, Promacot) Hydroxyzine - Cyclizine - Diphenhydramine - Dimenhydrinate - Meclizine - Promethazine (Pentazine, Phenergan, Promacot) - Hydroxyzine - Cannabinoids are used in patients with cachexia, cytotoxic nausea & vomiting or are unresponsive to other agents. Cannabis (Marijuana). Most patients prefer smoked or vaporized cannabis over pharmaceutical versions because they do not contain all 66 cannabinoids that are in cannabis, many of which have medicinal applications. CBD is a main cannabinoid not in Marinol or Cesamet. Dronabinol (Marinol). Ninety percent of sales are for cancer and AIDS patients. The other 10% of its sales thought to be for pain, Multiple Sclerosis and also for Alzheimer's disease. Nabilone (Cesamet). Put back on the market in late 2006. A Schedule II substance unlike Marinol which is Schedule III and cannabis which is Schedule I. Sativex is an oral spray containing THC and CBD. It is currently legal in Canada and a few countries in Europe but not in the U.S. yet. - Cannabis (Marijuana). Most patients prefer smoked or vaporized cannabis over pharmaceutical versions because they do not contain all 66 cannabinoids that are in cannabis, many of which have medicinal applications. CBD is a main cannabinoid not in Marinol or Cesamet. - Dronabinol (Marinol). Ninety percent of sales are for cancer and AIDS patients. The other 10% of its sales thought to be for pain, Multiple Sclerosis and also for Alzheimer's disease. - Nabilone (Cesamet). Put back on the market in late 2006. A Schedule II substance unlike Marinol which is Schedule III and cannabis which is Schedule I. - Sativex is an oral spray containing THC and CBD. It is currently legal in Canada and a few countries in Europe but not in the U.S. yet. - Benzodiazepines Midazolam given at the onset of anaesthesia has been shown in recent trials to be as effective as ondansetron, a 5HT3 antagonist in the prevention of post-operative nausea and vomiting. Further studies need to be undertaken. Lorazepam said to be very good as an adjunct treatment for nausea along with first line medications such as Compazine or Zofran. - Midazolam given at the onset of anaesthesia has been shown in recent trials to be as effective as ondansetron, a 5HT3 antagonist in the prevention of post-operative nausea and vomiting. Further studies need to be undertaken. - Lorazepam said to be very good as an adjunct treatment for nausea along with first line medications such as Compazine or Zofran. - Anticholinergics Hyoscine (also known as Scopolamine) - Hyoscine (also known as Scopolamine) - Steroids Dexamethasone given in low dose at the onset of a general anaesthetic for surgery is an effective anti-emetic. The specific mechanism of action is not fully understood. - Dexamethasone given in low dose at the onset of a general anaesthetic for surgery is an effective anti-emetic. The specific mechanism of action is not fully understood. - Other Trimethobenzamide; thought to work on the CTZ Ginger Emetrol also claimed to be an effective anti-emetic. Propofol given intravenously. It has been used in an acute care setting in hospital as a rescue therapy for emesis. Peppermint claimed to help nausea or stomach pain when added into a tea or peppermint candies. Muscimol purported as such [1] - Trimethobenzamide; thought to work on the CTZ - Ginger - Emetrol also claimed to be an effective anti-emetic. - Propofol given intravenously. It has been used in an acute care setting in hospital as a rescue therapy for emesis. - Peppermint claimed to help nausea or stomach pain when added into a tea or peppermint candies. - Muscimol purported as such [1] - Non-pharmaceutical therapies with some evidence of efficacy include acupuncture and hypnosis. All drugs have potential side effects. It is important to try to reduce the baseline risk of nausea and vomiting, particularly with respect to surgery.	https://www.wikidoc.org/index.php/Anti-emetic
1213b78cc3843d959091e69bb0c0258d726642dd	wikidoc	Antiseptic	Antiseptic Antiseptics (from Greek αντί - anti, '"against" + σηπτικός - septikos, "putrefactive") are antimicrobial substances that are applied to living tissue/skin to reduce the possibility of infection, sepsis, or putrefaction. They should generally be distinguished from antibiotics that destroy bacteria within the body, and from disinfectants, which destroy microorganisms found on non-living objects. Some antiseptics are true germicides, capable of destroying microbes (bacteriocidal), whilst others are bacteriostatic and only prevent or inhibit their growth. Antibacterials are antiseptics that only act against bacteria. # Use in surgery The widespread introduction of antiseptic surgical methods followed the publishing of the paper Antiseptic Principle of the Practice of Surgery in 1867 by Joseph Lister, inspired by Louis Pasteur's germ theory of putrefaction. In this paper he advocated the use of carbolic acid (phenol) as a method of ensuring that any germs present were killed. Some of this work was anticipated by: - Dr. George H Tichenor who experimented with the use of alcohol on wounds ca. 1861-1863, and subsequently marketed a product for this purpose known as "Dr. Tichenor's Patent Medicine " after the US Civil War. - Ignaz Semmelweis who published his work "The Cause, Concept and Prophylaxis of Childbed Fever" in 1861, summarizing experiments and observations since 1847. - Florence Nightingale, who contributed substantially to the report on the Royal Commission on the Health of the Army (1856–1857), based on her earlier work - Oliver Wendell Holmes, Sr., who published "The Contagiousness of Puerperal Fever" in 1843. and even the ancient Greek physicians Galen (ca 130–200 AD) and Hippocrates (ca 400 BC). There is even a Sumerian clay tablet dating from 2150 BC advocating the use of similar techniques. But every antiseptic, however good, is more or less toxic and irritating to a wounded surface. Hence it is that the antiseptic method has been replaced in the surgery of today by the aseptic method, which relies on keeping free from the invasion of bacteria rather than destroying them when present. # How it works For the growth of bacteria there must be a certain food supply, moisture, in most cases oxygen, and a certain minimum temperature (see bacteriology). These conditions have been specially studied and applied in connection with the preserving of food and in the ancient practice of embalming the dead, which is the earliest illustration of the systematic use of antiseptics. In early inquiries a great point was made of the prevention of putrefaction, and work was done in the way of finding how much of an agent must be added to a given solution, in order that the bacteria accidentally present might not develop. But for various reasons this was an inexact method, and today an antiseptic is judged by its effects on pure cultures of definite pathogenic celicular single helix microbes, and on their vegetative and spore forms. Their standardization has been affected in many instances, and a water solution of phenol of a certain fixed strength is now taken as the standard with which other antiseptics are compared. # Some common antiseptics - Alcohols Most commonly used are ethanol (60-90%), 1-propanol (60-70%) and 2-propanol/isopropanol (70-80%) or mixtures of these alcohols. They are commonly referred to as "surgical alcohol". Used to disinfect the skin before injections are given, often along with iodine (tincture of iodine) or some cationic surfactants (benzalkonium chloride 0.05 - 0.5%, chlorhexidine 0.2 - 4.0% or octenidine dihydrochloride 0.1 - 2.0%). - Quaternary ammonium compounds Also known as Quats or QAC's, include the chemicals benzalkonium chloride (BAC), cetyl trimethylammonium bromide (CTMB), cetylpyridinium chloride (Cetrim, CPC) and benzethonium chloride (BZT). Benzalkonium chloride is used in some pre-operative skin disinfectants (conc. 0.05 - 0.5%) and antiseptic towels. The antimicrobial activity of Quats is inactivated by anionic surfactants, such as soaps. Related disinfectants include chlorhexidine and octenidine. - Boric acid Used in suppositories to treat yeast infections of the vagina, in eyewashes, and as an antiviral to shorten the duration of cold sore attacks. Put into creams for burns. Also common in trace amounts in eye contact solution. Though it is popularly known as an antiseptic, it is in reality only a soothing fluid, and bacteria will flourish comfortably in contact with it. - Chlorhexidine Gluconate A biguanidine derivative, used in concentrations of 0.5 - 4.0% alone or in lower concentrations in combination with other compounds, such as alcohols. Used as a skin antiseptic and to treat inflammation of the gums (gingivitis). The microbicidal action is somewhat slow, but remanent. It is a cationic surfactant, similar to Quats. - Hydrogen peroxide Used as a 6% (20Vols) solution to clean and deodorize wounds and ulcers. More common 1% or 2% solutions of hydrogen peroxide have been used in household first aid for scrapes, etc. However, even this less potent form is no longer recommended for typical wound care as the strong oxidization causes scar formation and increases healing time. Gentle washing with mild soap and water or rinsing a scrape with sterile saline is a better practice. - Iodine Usually used in an alcoholic solution (called tincture of iodine) or as Lugol's iodine solution as a pre and post-operative antiseptic. No longer recommended to disinfect minor wounds because it induces scar tissue formation and increases healing time. Gentle washing with mild soap and water or rinsing a scrape with sterile saline is a better practice. Novel iodine antiseptics containing povidone-iodine (an iodophor, complex of povidone, a water-soluble polymer, with triiodide anions I3-, containing about 10% of active iodine) are far better tolerated, don't affect wound healing negativelly and leave a depot of active iodine, creating the so-called "remanent," or persistent, effect. The great advantage of iodine antiseptics is the widest scope of antimicrobial activity, killing all principial pathogenes and given enough time even spores, which are considered to be the most difficult form of microorganisms to be inactivated by disinfectants and antiseptics. - Mercurochrome Not recognized as safe and effective by the U.S. Food and Drug Administration (FDA) due to concerns about its mercury content. Another obsolete organomercury antiseptics include bis-(fenylmercury) monohydrogenborate (Famosept). - Octenidine dihydrochloride A cationic surfactant and bis-(dihydropyridinyl)-decane derivative, used in concentrations of 0.1 - 2.0%. It is similar in its action to the Quats, but is of somewhat broader spectrum of activity. Octenidine is currently increasingly used in continental Europe as a QAC's and chlorhexidine (with respect to its slow action and concerns about the carcinogenic impurity 4-chloroaniline) substitute in water- or alcohol-based skin, mucosa and wound antiseptic. In aqueous formulations, it is often potentiated with addition of 2-phenoxyethanol. - Phenol (carbolic acid) compounds Phenol is germicidal in strong solution, inhibitory in weaker ones. Used as a "scrub" for pre-operative hand cleansing. Used in the form of a powder as an antiseptic baby powder, where it is dusted onto the navel as it heals. Also used in mouthwashes and throat lozenges, where it has a painkilling effect as well as an antiseptic one. Example: TCP. Other phenolic antiseptics include historically important, but today rarely used (sometimes in dental surgery) thymol, today obsolete hexachlorophene, still used triclosan and sodium 3,5-dibromo-4-hydroxybenzenesulfonate (Dibromol). - Sodium chloride Used as a general cleanser. Also used as an antiseptic mouthwash. Only a weak antiseptic effect, due to hyperosmolality of the solution above 0.9%. - Sodium hypochlorite Used in the past, diluted, neutralized and combined with potassium permanganate in the Daquin's solution. It is now used only as disinfectant. # Negative effects Stuart B. Levy, in a presentation to the 2000 Emerging Infectious Diseases Conference, expressed concern that the overuse of antiseptic and antibacterial agents might lead to an increase in dangerous, resistant strains of bacteria. # Endogenous The body produces its own antiseptics, which are a part of the chemical barriers of the immune system. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antiseptic. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens. In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens.	Antiseptic Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Antiseptics (from Greek αντί - anti, '"against" + σηπτικός - septikos, "putrefactive") are antimicrobial substances that are applied to living tissue/skin to reduce the possibility of infection, sepsis, or putrefaction. They should generally be distinguished from antibiotics that destroy bacteria within the body, and from disinfectants, which destroy microorganisms found on non-living objects. Some antiseptics are true germicides, capable of destroying microbes (bacteriocidal), whilst others are bacteriostatic and only prevent or inhibit their growth. Antibacterials are antiseptics that only act against bacteria. # Use in surgery The widespread introduction of antiseptic surgical methods followed the publishing of the paper Antiseptic Principle of the Practice of Surgery in 1867 by Joseph Lister, inspired by Louis Pasteur's germ theory of putrefaction. In this paper he advocated the use of carbolic acid (phenol) as a method of ensuring that any germs present were killed. Some of this work was anticipated by: - Dr. George H Tichenor who experimented with the use of alcohol on wounds ca. 1861-1863, and subsequently marketed a product for this purpose known as "Dr. Tichenor's Patent Medicine " after the US Civil War. - Ignaz Semmelweis who published his work "The Cause, Concept and Prophylaxis of Childbed Fever" in 1861, summarizing experiments and observations since 1847.[1] - Florence Nightingale, who contributed substantially to the report on the Royal Commission on the Health of the Army (1856–1857), based on her earlier work - Oliver Wendell Holmes, Sr., who published "The Contagiousness of Puerperal Fever" in 1843. and even the ancient Greek physicians Galen (ca 130–200 AD) and Hippocrates (ca 400 BC). There is even a Sumerian clay tablet dating from 2150 BC advocating the use of similar techniques.[2] But every antiseptic, however good, is more or less toxic and irritating to a wounded surface. Hence it is that the antiseptic method has been replaced in the surgery of today by the aseptic method, which relies on keeping free from the invasion of bacteria rather than destroying them when present. # How it works For the growth of bacteria there must be a certain food supply, moisture, in most cases oxygen, and a certain minimum temperature (see bacteriology). These conditions have been specially studied and applied in connection with the preserving of food and in the ancient practice of embalming the dead, which is the earliest illustration of the systematic use of antiseptics. In early inquiries a great point was made of the prevention of putrefaction, and work was done in the way of finding how much of an agent must be added to a given solution, in order that the bacteria accidentally present might not develop. But for various reasons this was an inexact method, and today an antiseptic is judged by its effects on pure cultures of definite pathogenic celicular single helix microbes, and on their vegetative and spore forms. Their standardization has been affected in many instances, and a water solution of phenol of a certain fixed strength is now taken as the standard with which other antiseptics are compared. # Some common antiseptics - Alcohols Most commonly used are ethanol (60-90%), 1-propanol (60-70%) and 2-propanol/isopropanol (70-80%) or mixtures of these alcohols. They are commonly referred to as "surgical alcohol". Used to disinfect the skin before injections are given, often along with iodine (tincture of iodine) or some cationic surfactants (benzalkonium chloride 0.05 - 0.5%, chlorhexidine 0.2 - 4.0% or octenidine dihydrochloride 0.1 - 2.0%). - Quaternary ammonium compounds Also known as Quats or QAC's, include the chemicals benzalkonium chloride (BAC), cetyl trimethylammonium bromide (CTMB), cetylpyridinium chloride (Cetrim, CPC) and benzethonium chloride (BZT). Benzalkonium chloride is used in some pre-operative skin disinfectants (conc. 0.05 - 0.5%) and antiseptic towels. The antimicrobial activity of Quats is inactivated by anionic surfactants, such as soaps. Related disinfectants include chlorhexidine and octenidine. - Boric acid Used in suppositories to treat yeast infections of the vagina, in eyewashes, and as an antiviral to shorten the duration of cold sore attacks. Put into creams for burns. Also common in trace amounts in eye contact solution. Though it is popularly known as an antiseptic, it is in reality only a soothing fluid, and bacteria will flourish comfortably in contact with it. - Chlorhexidine Gluconate A biguanidine derivative, used in concentrations of 0.5 - 4.0% alone or in lower concentrations in combination with other compounds, such as alcohols. Used as a skin antiseptic and to treat inflammation of the gums (gingivitis). The microbicidal action is somewhat slow, but remanent. It is a cationic surfactant, similar to Quats. - Hydrogen peroxide Used as a 6% (20Vols) solution to clean and deodorize wounds and ulcers. More common 1% or 2% solutions of hydrogen peroxide have been used in household first aid for scrapes, etc. However, even this less potent form is no longer recommended for typical wound care as the strong oxidization causes scar formation and increases healing time. Gentle washing with mild soap and water or rinsing a scrape with sterile saline is a better practice. - Iodine Usually used in an alcoholic solution (called tincture of iodine) or as Lugol's iodine solution as a pre and post-operative antiseptic. No longer recommended to disinfect minor wounds because it induces scar tissue formation and increases healing time. Gentle washing with mild soap and water or rinsing a scrape with sterile saline is a better practice. Novel iodine antiseptics containing povidone-iodine (an iodophor, complex of povidone, a water-soluble polymer, with triiodide anions I3-, containing about 10% of active iodine) are far better tolerated, don't affect wound healing negativelly and leave a depot of active iodine, creating the so-called "remanent," or persistent, effect. The great advantage of iodine antiseptics is the widest scope of antimicrobial activity, killing all principial pathogenes and given enough time even spores, which are considered to be the most difficult form of microorganisms to be inactivated by disinfectants and antiseptics. - Mercurochrome Not recognized as safe and effective by the U.S. Food and Drug Administration (FDA) due to concerns about its mercury content. Another obsolete organomercury antiseptics include bis-(fenylmercury) monohydrogenborate (Famosept). - Octenidine dihydrochloride A cationic surfactant and bis-(dihydropyridinyl)-decane derivative, used in concentrations of 0.1 - 2.0%. It is similar in its action to the Quats, but is of somewhat broader spectrum of activity. Octenidine is currently increasingly used in continental Europe as a QAC's and chlorhexidine (with respect to its slow action and concerns about the carcinogenic impurity 4-chloroaniline) substitute in water- or alcohol-based skin, mucosa and wound antiseptic. In aqueous formulations, it is often potentiated with addition of 2-phenoxyethanol. - Phenol (carbolic acid) compounds Phenol is germicidal in strong solution, inhibitory in weaker ones. Used as a "scrub" for pre-operative hand cleansing. Used in the form of a powder as an antiseptic baby powder, where it is dusted onto the navel as it heals. Also used in mouthwashes and throat lozenges, where it has a painkilling effect as well as an antiseptic one. Example: TCP. Other phenolic antiseptics include historically important, but today rarely used (sometimes in dental surgery) thymol, today obsolete hexachlorophene, still used triclosan and sodium 3,5-dibromo-4-hydroxybenzenesulfonate (Dibromol). - Sodium chloride Used as a general cleanser. Also used as an antiseptic mouthwash. Only a weak antiseptic effect, due to hyperosmolality of the solution above 0.9%. - Sodium hypochlorite Used in the past, diluted, neutralized and combined with potassium permanganate in the Daquin's solution. It is now used only as disinfectant. # Negative effects Stuart B. Levy, in a presentation to the 2000 Emerging Infectious Diseases Conference, expressed concern that the overuse of antiseptic and antibacterial agents might lead to an increase in dangerous, resistant strains of bacteria.[2] # Endogenous The body produces its own antiseptics, which are a part of the chemical barriers of the immune system. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins.[3] Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antiseptic.[4][5] Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens.[6][7] In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens.	https://www.wikidoc.org/index.php/Antibacterial
a7a1d46decba792b7cd37b72dfcbd27b8d8247c4	wikidoc	Antibiotic	Antibiotic # Overview An antibiotic is a chemical compound that inhibits or abolishes the growth of microorganisms, such as bacteria, fungi, or protozoans. The term originally referred to any agent with biological activity against living organisms; however, "antibiotic" now is used to refer to substances with anti-bacterial, anti-fungal, or anti-parasitical activity. The first antibiotic compounds used in modern medicine were produced and isolated from living organisms, such as the penicillin class produced by fungi in the genus Penicillium, or streptomycin from bacteria of the genus Streptomyces. With advances in organic chemistry many antibiotics are now also obtained by chemical synthesis, such as the sulfa drugs. Many antibiotics are relatively small molecules with a molecular weight less than 2000 Da. Unlike previous treatments for infections, which often consisted of administering chemical compounds such as strychnine and arsenic, with high toxicity also against mammals, antibiotics from microbes had no or few side effects and high effective target activity. Most anti-bacterial antibiotics do not have activity against viruses, fungi, or other microbes. Anti-bacterial antibiotics can be categorized based on their target specificity: "narrow-spectrum" antibiotics target particular types of bacteria, such as Gram-negative or Gram-positive bacteria, while broad-spectrum antibiotics affect a wide range of bacteria. The effectiveness of individual antibiotics varies with the location of the infection, the ability of the antibiotic to reach the site of infection, and the ability of the microbe to inactivate or excrete the antibiotic. Some anti-bacterial antibiotics destroy bacteria (bactericidal), whereas others prevent bacteria from multiplying (bacteriostatic). Oral antibiotics are simply ingested, while intravenous antibiotics are used in more serious cases, such as deep-seated systemic infections. Antibiotics may also sometimes be administered topically, as with eye drops or ointments. In the last few years, three new classes of antibiotics have been brought into clinical use. This follows a 40-year hiatus in discovering new classes of antibiotic compounds. These new antibiotics are of the following three classes: cyclic lipopeptides (daptomycin), glycylcyclines (tigecycline), and oxazolidinones (linezolid). Tigecycline is a broad-spectrum antibiotic, while the two others are used for gram-positive infections. These developments show promise as a means to counteract the growing bacterial resistance to existing antibiotics. # History Although potent antibiotic compounds for treatment of human diseases caused by bacteria (such as tuberculosis, bubonic plague, or leprosy) were not isolated and identified until the twentieth century, the first known use of antibiotics was by the ancient Chinese over 2,500 years ago. Many other ancient cultures, including the ancient Egyptians and ancient Greeks already used molds and plants to treat infections, owing to the production of antibiotic substances by these organisms. At that time, however, the compounds having antibiotic activity and present in moulds or plants were unknown. The antibiotic properties of Penicillium sp. were first described in France by Ernest Duchesne in 1897. However, his work went by without much notice from the scientific community until Alexander Fleming's discovery of Penicillin (see below). Modern research on antibiotic therapy began in Germany with the development of the narrow-spectrum antibiotic Salvarsan by Paul Ehrlich in 1909, for the first time allowing an efficient treatment of the then-widespread problem of Syphilis. The drug, which was also effective against other spirochaetal infections, is no longer in use in modern medicine. Antibiotics were further developed in Britain following the re-discovery of Penicillin in 1928 by Alexander Fleming. More than ten years later, Ernst Chain and Howard Florey became interested in his work, and came up with the purified form of penicillin. The three shared the 1945 Nobel Prize in Medicine. "Antibiotic" was originally used to refer only to substances extracted from a fungus or other microorganism, but has come to include also the many synthetic and semi-synthetic drugs that have antibacterial effects. # Classes of antibiotics At the highest level, antibiotics can be classified as either bactericidal or bacteriostatic. Bactericidals kill bacteria directly where bacteriostatics prevent them from dividing. However, these classifications are based on laboratory behavior; in practice, both of these are capable of ending a bacterial infection. # Production Since the first pioneering efforts of Florey and Chain in 1939, the importance of antibiotics to medicine has led to much research into discovering and producing them. The process of production usually involves screening of wide ranges of microorganisms, testing and modification. Production is carried out using fermentation; a process that is important in anaerobic conditions when there is no oxidative phosphorylation to maintain the production of adenosine triphosphate (ATP) by glycolysis. # Side effects Possible side effects are varied, depend on the antibiotics used and the microbial organisms targeted. Adverse effects can range from fever and nausea to major allergic reactions including photodermatitis. One of the more common side effects is diarrhea, sometimes caused by the anaerobic bacterium Clostridium difficile, which results from the antibiotic disrupting the normal balance of the intestinal flora, Such overgrowth of pathogenic bacteria may be alleviated by ingesting probiotics during a course of antibiotics. An antibiotic-induced disruption of the population of the bacteria normally present as constituents of the normal vaginal flora may also occur, and may lead to overgrowth of yeast species of the genus Candida in the vulvo-vaginal area. Other side effects can result from interaction with other drugs, such as elevated risk of tendon damage from administration of a quinolone antibiotic with a systemic corticosteroid. It is a common assertion that some antibiotics can interfere with the efficiency of birth control pills. Although there remain few known cases of complication, the majority of antibiotics do not interfere with contraception, despite widespread misinformation to the contrary. # Antibiotic misuse Common forms of antibiotic misuse include failure to take the entire prescribed course of the antibiotic, or failure to rest for sufficient recovery allowing clearance from the infecting organism. These practices may cause the development of bacterial populations with antibiotic resistance. Inappropriate antibiotic treatment is another common form of antibiotic misuse. A common example is the use of antibacterial antibiotics to treat viral infections such as the common cold. ## Animals It is estimated that greater than 50% of the antibiotics used in U.S. are given to feed animals (e.g. chickens, pigs and cattle) in the absence of disease. Antibiotic use in food animal production has been associated with the emergence of antibiotic-resistant strains of bacteria including Salmonella spp., Campylobacter spp., Escherichia coli, and Enterococcus spp. Evidence from some US and European studies suggest that these resistant bacteria cause infections in humans that do not respond to commonly prescribed antibiotics. In response to these practices and attendant problems, several organizations (e.g. The American Society for Microbiology (ASM), American Public Health Association (APHA) and the American Medical Association (AMA)) have called for restrictions on antibiotic use in food animal production and an end to all non-therapeutic uses. However, delays in regulatory and legislative actions to limit the use of antibiotics are common, and may include resistance to these changes by industries using or selling antibiotics, as well as time spend on research to establish causal links between antibiotic use and emergence of untreatable bacterial diseases. Today, there are two federal bills (S.742 and H.R. 2562) aimed at phasing out non-therapeutic antibiotics in US food animal production. These bills are endorsed by public health and medical organizations including the American Nurses Association (ANA), the American Academy of Pediatrics (AAP), and the American Public Health Association (APHA). ## Humans One study on respiratory tract infections found "physicians were more likely to prescribe antibiotics to patients who they believed expected them, although they correctly identified only about 1 in 4 of those patients". Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescribing of antibiotics. Delaying antibiotics for 48 hours while observing for spontaneous resolution of respiratory tract infections may reduce antibiotic usage; however, this strategy may reduce patient satisfaction. Excessive use of prophylactic antibiotics in travelers may also be classified as misuse. # Antibiotic resistance Use or misuse of antibiotics may result in the development of antibiotic resistance by the infecting organisms, similar to the development of pesticide resistance in insects. Evolutionary theory of genetic selection requires that as close as possible to 100% of the infecting organisms be killed off to avoid selection of resistance; if a small subset of the population survives the treatment and is allowed to multiply, the average susceptibility of this new population to the compound will be much less than that of the original population, since they have descended from those few organisms which survived the original treatment. This survival often results from an inheritable resistance to the compound which was infrequent in the original population but is now much more frequent in the descendants thus selected entirely from those originally infrequent resistant organisms. Antibiotic resistance has become a serious problem in both the developed and underdeveloped nations. By 1984 half of the people with active tuberculosis in the United States had a strain that resisted at least one antibiotic. In certain settings, such as hospitals and some child-care locations, the rate of antibiotic resistance is so high that the normal, low cost antibiotics are virtually useless for treatment of frequently seen infections. This leads to more frequent use of newer and more expensive compounds, which in turn leads inexorably to the rise of resistance to those drugs, and a race to discover new and different antibiotics ensues, just to keep us from losing ground in the battle against infection. The fear is that we will eventually fail to keep up in this race, and the time when people did not fear life-threatening bacterial infections will be just a memory of a golden era. Another example of selection is Staphylococcus aureus, which could be treated successfully with penicillin in the 1940s and 1950s. At present, nearly all strains are resistant to penicillin, and many are resistant to nafcillin, leaving only a narrow selection of drugs such as vancomycin useful for treatment. The situation is worsened by the fact that genes coding for antibiotic resistance can be transferred between bacteria via plasmids, making it possible for bacteria never exposed to an antibiotic to acquire resistance from those which have. The problem of antibiotic resistance is worsened when antibiotics are used to treat disorders in which they have no efficacy, such as the common cold or other viral complaints, and when they are used widely as prophylaxis rather than treatment (as in, for example, animal feeds), because this exposes more bacteria to selection for resistance. # Beyond antibiotics The comparative ease of identifying compounds which safely cured bacterial infections was more difficult to duplicate in treatments of fungal and viral infections. Antibiotic research led to great strides in the knowledge of biochemistry, establishing large differences between the cellular and molecular physiology of the bacterial cell and that of the mammalian cell. This explained the observation that many compounds that are toxic to bacteria are non-toxic to human cells. In contrast, the basic biochemistries of the fungal cell and the mammalian cell are much more similar. This restricts the development and use of therapeutic compounds that attack a fungal cell, while not harming mammalian cells. Similar problems exist in antibiotic treatments of viral diseases. Human viral metabolic biochemistry is very closely similar to human biochemistry, and the possible targets of antiviral compounds are restricted to very few components unique to a mammalian virus. Research into bacteriophages for use as antibiotics is presently ongoing. Several types of bacteriophage appear to exist that are specific for each bacterial taxonomic group or species. Research into bacteriophages for medicinal use is just beginning, but has led to advances in microscopic imaging. While bacteriophages provide a possible solution to the problem of antibiotic resistance, there is no clinical evidence yet that they can be deployed as therapeutic agents to cure disease. Phage therapy has been used in the past on humans in the US and Europe during the 1920s and 1930s, but these treatments had mixed results. With the discovery of penicillin in the 1940s, Europe and the US changed therapeutic strategies to using antibiotics. However, in the former Soviet Union phage therapies continued to be studied. In the Republic of Georgia, the Eliava Institute of Bacteriophage, Microbiology & Virology continues to research the use of phage therapy. Various companies and foundations in North America and Europe are currently researching phage therapies.	Antibiotic Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An antibiotic is a chemical compound that inhibits or abolishes the growth of microorganisms, such as bacteria, fungi, or protozoans. The term originally referred to any agent with biological activity against living organisms; however, "antibiotic" now is used to refer to substances with anti-bacterial, anti-fungal, or anti-parasitical activity. The first antibiotic compounds used in modern medicine were produced and isolated from living organisms, such as the penicillin class produced by fungi in the genus Penicillium, or streptomycin from bacteria of the genus Streptomyces. With advances in organic chemistry many antibiotics are now also obtained by chemical synthesis, such as the sulfa drugs. Many antibiotics are relatively small molecules with a molecular weight less than 2000 Da. Unlike previous treatments for infections, which often consisted of administering chemical compounds such as strychnine and arsenic, with high toxicity also against mammals, antibiotics from microbes had no or few side effects and high effective target activity. Most anti-bacterial antibiotics do not have activity against viruses, fungi, or other microbes. Anti-bacterial antibiotics can be categorized based on their target specificity: "narrow-spectrum" antibiotics target particular types of bacteria, such as Gram-negative or Gram-positive bacteria, while broad-spectrum antibiotics affect a wide range of bacteria. The effectiveness of individual antibiotics varies with the location of the infection, the ability of the antibiotic to reach the site of infection, and the ability of the microbe to inactivate or excrete the antibiotic. Some anti-bacterial antibiotics destroy bacteria (bactericidal), whereas others prevent bacteria from multiplying (bacteriostatic). Oral antibiotics are simply ingested, while intravenous antibiotics are used in more serious cases, such as deep-seated systemic infections. Antibiotics may also sometimes be administered topically, as with eye drops or ointments. In the last few years, three new classes of antibiotics have been brought into clinical use. This follows a 40-year hiatus in discovering new classes of antibiotic compounds. These new antibiotics are of the following three classes: cyclic lipopeptides (daptomycin), glycylcyclines (tigecycline), and oxazolidinones (linezolid). Tigecycline is a broad-spectrum antibiotic, while the two others are used for gram-positive infections. These developments show promise as a means to counteract the growing bacterial resistance to existing antibiotics. # History Although potent antibiotic compounds for treatment of human diseases caused by bacteria (such as tuberculosis, bubonic plague, or leprosy) were not isolated and identified until the twentieth century, the first known use of antibiotics was by the ancient Chinese over 2,500 years ago.[1] Many other ancient cultures, including the ancient Egyptians and ancient Greeks already used molds and plants to treat infections, owing to the production of antibiotic substances by these organisms. At that time, however, the compounds having antibiotic activity and present in moulds or plants were unknown. The antibiotic properties of Penicillium sp. were first described in France by Ernest Duchesne in 1897. However, his work went by without much notice from the scientific community until Alexander Fleming's discovery of Penicillin (see below). Modern research on antibiotic therapy began in Germany with the development of the narrow-spectrum antibiotic Salvarsan by Paul Ehrlich in 1909, for the first time allowing an efficient treatment of the then-widespread problem of Syphilis. The drug, which was also effective against other spirochaetal infections, is no longer in use in modern medicine. Antibiotics were further developed in Britain following the re-discovery of Penicillin in 1928 by Alexander Fleming. More than ten years later, Ernst Chain and Howard Florey became interested in his work, and came up with the purified form of penicillin. The three shared the 1945 Nobel Prize in Medicine. "Antibiotic" was originally used to refer only to substances extracted from a fungus or other microorganism, but has come to include also the many synthetic and semi-synthetic drugs that have antibacterial effects. # Classes of antibiotics At the highest level, antibiotics can be classified as either bactericidal or bacteriostatic. Bactericidals kill bacteria directly where bacteriostatics prevent them from dividing. However, these classifications are based on laboratory behavior; in practice, both of these are capable of ending a bacterial infection. # Production Since the first pioneering efforts of Florey and Chain in 1939, the importance of antibiotics to medicine has led to much research into discovering and producing them. The process of production usually involves screening of wide ranges of microorganisms, testing and modification. Production is carried out using fermentation; a process that is important in anaerobic conditions when there is no oxidative phosphorylation to maintain the production of adenosine triphosphate (ATP) by glycolysis. # Side effects Possible side effects are varied, depend on the antibiotics used and the microbial organisms targeted. Adverse effects can range from fever and nausea to major allergic reactions including photodermatitis. One of the more common side effects is diarrhea, sometimes caused by the anaerobic bacterium Clostridium difficile, which results from the antibiotic disrupting the normal balance of the intestinal flora,[3] Such overgrowth of pathogenic bacteria may be alleviated by ingesting probiotics during a course of antibiotics. An antibiotic-induced disruption of the population of the bacteria normally present as constituents of the normal vaginal flora may also occur, and may lead to overgrowth of yeast species of the genus Candida in the vulvo-vaginal area. [4] Other side effects can result from interaction with other drugs, such as elevated risk of tendon damage from administration of a quinolone antibiotic with a systemic corticosteroid. It is a common assertion that some antibiotics can interfere with the efficiency of birth control pills. Although there remain few known cases of complication, the majority of antibiotics do not interfere with contraception, despite widespread misinformation to the contrary.[5] # Antibiotic misuse Common forms of antibiotic misuse include failure to take the entire prescribed course of the antibiotic, or failure to rest for sufficient recovery allowing clearance from the infecting organism. These practices may cause the development of bacterial populations with antibiotic resistance. Inappropriate antibiotic treatment is another common form of antibiotic misuse. A common example is the use of antibacterial antibiotics to treat viral infections such as the common cold. ## Animals It is estimated that greater than 50% of the antibiotics used in U.S. are given to feed animals (e.g. chickens, pigs and cattle) in the absence of disease.[6] Antibiotic use in food animal production has been associated with the emergence of antibiotic-resistant strains of bacteria including Salmonella spp., Campylobacter spp., Escherichia coli, and Enterococcus spp. Evidence from some US and European studies suggest that these resistant bacteria cause infections in humans that do not respond to commonly prescribed antibiotics. In response to these practices and attendant problems, several organizations (e.g. The American Society for Microbiology (ASM), American Public Health Association (APHA) and the American Medical Association (AMA)) have called for restrictions on antibiotic use in food animal production and an end to all non-therapeutic uses. However, delays in regulatory and legislative actions to limit the use of antibiotics are common, and may include resistance to these changes by industries using or selling antibiotics, as well as time spend on research to establish causal links between antibiotic use and emergence of untreatable bacterial diseases. Today, there are two federal bills (S.742 and H.R. 2562) aimed at phasing out non-therapeutic antibiotics in US food animal production. These bills are endorsed by public health and medical organizations including the American Nurses Association (ANA), the American Academy of Pediatrics (AAP), and the American Public Health Association (APHA). ## Humans One study on respiratory tract infections found "physicians were more likely to prescribe antibiotics to patients who they believed expected them, although they correctly identified only about 1 in 4 of those patients".[7] Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescribing of antibiotics. [8] Delaying antibiotics for 48 hours while observing for spontaneous resolution of respiratory tract infections may reduce antibiotic usage; however, this strategy may reduce patient satisfaction.[9] Excessive use of prophylactic antibiotics in travelers may also be classified as misuse. # Antibiotic resistance Use or misuse of antibiotics may result in the development of antibiotic resistance by the infecting organisms, similar to the development of pesticide resistance in insects. Evolutionary theory of genetic selection requires that as close as possible to 100% of the infecting organisms be killed off to avoid selection of resistance; if a small subset of the population survives the treatment and is allowed to multiply, the average susceptibility of this new population to the compound will be much less than that of the original population, since they have descended from those few organisms which survived the original treatment. This survival often results from an inheritable resistance to the compound which was infrequent in the original population but is now much more frequent in the descendants thus selected entirely from those originally infrequent resistant organisms. Antibiotic resistance has become a serious problem in both the developed and underdeveloped nations. By 1984 half of the people with active tuberculosis in the United States had a strain that resisted at least one antibiotic. In certain settings, such as hospitals and some child-care locations, the rate of antibiotic resistance is so high that the normal, low cost antibiotics are virtually useless for treatment of frequently seen infections. This leads to more frequent use of newer and more expensive compounds, which in turn leads inexorably to the rise of resistance to those drugs, and a race to discover new and different antibiotics ensues, just to keep us from losing ground in the battle against infection. The fear is that we will eventually fail to keep up in this race, and the time when people did not fear life-threatening bacterial infections will be just a memory of a golden era. Another example of selection is Staphylococcus aureus, which could be treated successfully with penicillin in the 1940s and 1950s. At present, nearly all strains are resistant to penicillin, and many are resistant to nafcillin, leaving only a narrow selection of drugs such as vancomycin useful for treatment. The situation is worsened by the fact that genes coding for antibiotic resistance can be transferred between bacteria via plasmids, making it possible for bacteria never exposed to an antibiotic to acquire resistance from those which have. The problem of antibiotic resistance is worsened when antibiotics are used to treat disorders in which they have no efficacy, such as the common cold or other viral complaints, and when they are used widely as prophylaxis rather than treatment (as in, for example, animal feeds), because this exposes more bacteria to selection for resistance. # Beyond antibiotics The comparative ease of identifying compounds which safely cured bacterial infections was more difficult to duplicate in treatments of fungal and viral infections. Antibiotic research led to great strides in the knowledge of biochemistry, establishing large differences between the cellular and molecular physiology of the bacterial cell and that of the mammalian cell. This explained the observation that many compounds that are toxic to bacteria are non-toxic to human cells. In contrast, the basic biochemistries of the fungal cell and the mammalian cell are much more similar. This restricts the development and use of therapeutic compounds that attack a fungal cell, while not harming mammalian cells. Similar problems exist in antibiotic treatments of viral diseases. Human viral metabolic biochemistry is very closely similar to human biochemistry, and the possible targets of antiviral compounds are restricted to very few components unique to a mammalian virus. Research into bacteriophages for use as antibiotics is presently ongoing. Several types of bacteriophage appear to exist that are specific for each bacterial taxonomic group or species. Research into bacteriophages for medicinal use is just beginning, but has led to advances in microscopic imaging.[10] While bacteriophages provide a possible solution to the problem of antibiotic resistance, there is no clinical evidence yet that they can be deployed as therapeutic agents to cure disease. Phage therapy has been used in the past on humans in the US and Europe during the 1920s and 1930s, but these treatments had mixed results. With the discovery of penicillin in the 1940s, Europe and the US changed therapeutic strategies to using antibiotics. However, in the former Soviet Union phage therapies continued to be studied. In the Republic of Georgia, the Eliava Institute of Bacteriophage, Microbiology & Virology continues to research the use of phage therapy. Various companies and foundations in North America and Europe are currently researching phage therapies.	https://www.wikidoc.org/index.php/Antibacterials
01293c5fd5b011aefd6f738860f59cbf00bdfffb	wikidoc	Antibodies	Antibodies # Overview Antibodies are Y-shaped proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. They are made of a few basic structural units called chains; each antibody has two large heavy chains and two small light chains. There are several different types of antibody heavy chain, and several different kinds of antibodies, which are grouped into different isotypes based on which heavy chain they possess. Five different antibody isotypes are known in mammals, which perform different roles, and help direct the appropriate immune response for each different type of foreign object they encounter. Although the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies with slightly different tip structures to exist. Each of these variants can bind to a different target, known as an antigen. This huge diversity of antibodies allows the immune system to recognize an equally wide diversity of antigens. The unique part of the antigen recognized by an antibody is called an epitope. These epitopes fit precisely with their antibody, similar to a key fitting into a lock, in a highly specific interaction that allows antibodies to identify and bind only their unique antigen in the midst of the millions of different molecules that make up an organism. Recognition of an antigen by an antibody tags it for attack by other parts of the immune system. Antibodies can also neutralize targets directly by, for example, binding to a part of a pathogen that it needs to cause an infection. The large and diverse population of antibodies is generated by random combinations of a set of gene segments that encode different antigen binding sites (or paratopes), followed by random mutations in this area of the antibody gene, which create further diversity. Antibody genes also re-organize in a process called class switching that changes the base of the heavy chain to another, creating a different isotype of the antibody that retains the antigen specific variable region. This allows a single antibody to be used by several different parts of the immune system. Antibodies occur in two forms: a soluble form secreted into the blood and tissue fluids, and a membrane-bound form attached to the surface of a B cell that is called the B cell receptor (BCR). The BCR allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation. Activated B cells differentiate into either antibody generating factories called plasma cells that secrete soluble antibody, or into memory cells that survive in the body for years afterwards to allow the immune system to remember an antigen and respond faster upon future exposures. Antibodies are, therefore, an essential component of the adaptive immune system that learns, adapts and remembers responses to invading pathogens. Production of antibodies is the main function of the humoral immune system. # Isotypes Antibodies can come in different forms known as isotypes or classes. In mammals there are five antibody isotypes known as IgA, IgD, IgE,IgG and IgM. They are each named with an "Ig" prefix that stands for immunoglobulin, another name for antibody, and differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table. The antibody isotype of a B cell changes during the cell's development and activation. Immature B cells, which have never been exposed to antigen, are known as naïve B cells and express only the IgM isotype in a cell surface bound form. B cells begin to express both IgM and IgD when they reach maturity - the co-expression of both these immunoglobulin isotypes renders the B cell 'mature' and ready to respond to antigen. B cell activation follows engagement of the cell bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody producing cell called a plasma cell. In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane-bound form. Some daughter cells of the activated B cells undergo isotype switching, a mechanism that causes the production of antiodies to change from IgM or IgD to the other antibody isotypes, IgE, IgA or IgG, that have defined roles in the immune system. # Structure Antibodies are heavy globular plasma proteins that are also known as immunoglobulins. They have sugar chains added to some of their amino acid residues. In other words, antibodies are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM. ## Immunoglobulin domains The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or IgV, and constant or IgC) according to their size and function. They possess a characteristic immunoglobulin fold in which two beta sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. ## Heavy chain There are five types of mammalian Ig heavy chain denoted by the Greek letters: α, δ, ε, γ, and μ. The type of heavy chain present defines the class of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region and the variable region. The constant region is identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem (in a line) Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. ## Light chain In mammals there are only two types of light chain, which are called lambda (λ) and kappa (κ). A light chain has two successive domains: one constant domain and one variable domain. The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. Other types of light chains, such as the iota (ι) chain, are found in lower vertebrates like Chondrichthyes and Teleostei. ## Fab and Fc Regions Some parts of an antibody have unique functions. The tip of the Y, for example, contains the site that binds antigen and, therefore, recognizes specific foreign objects. This region of the antibody is called the Fab (fragment, antigen binding) region. It is composed of one constant and one variable domain from each heavy and light chain of the antibody. The paratope is shaped at the amino terminal end of the antibody monomer by the variable domains from the heavy and light chains. The base of the Y plays a role in modulating immune cell activity. This region is called the Fc (Fragment, crystallizable) region, and is composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody. By binding to specific proteins the Fc region ensures that each antibody generates an appropriate immune response for a given antigen. The Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins. By doing this, it mediates different physiological effects including opsonization, cell lysis, and degranulation of mast cells, basophils and eosinophils. # Function Since antibodies exist freely in the bloodstream, they are said to be part of the humoral immune system. Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen, a virus hull protein fragment, for example. Antibodies contribute to immunity in three main ways: they can prevent pathogens from entering or damaging cells by binding to them; they can stimulate removal of a pathogen by macrophages and other cells by coating the pathogen; and they can trigger direct pathogen destruction by stimulating other immune responses such as the complement pathway. ## Activation of complement Antibodies that bind to surface antigens on, for example a bacterium, attract the first component of the complement cascade with their Fc region and initiate activation of the "classical" complement system. This results in the killing of bacteria in two ways. First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization; these phagocytes are attracted by certain complement molecules generated in the complement cascade. Secondly, some complement system components form a membrane attack complex to assist antibodies to kill the bacterium directly. ## Activation of effector cells To combat pathogens that replicate outside cells antibodies bind to pathogens to link them together, causing them to agglutinate. Since an antibody possesses at least two paratopes it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region. Those cells which recognize coated pathogens have Fc receptors which, as the name suggests, interacts with the Fc region of IgA, IgG, and IgE antibodies. The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell; phagocytes will phagocytose, mast cells and neutrophils will degranulate, natural killer cells will release cytokines and cytotoxic molecules; that will ultimately result in destruction of the invading microbe. The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens. # Immunoglobulin diversity Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies; their amino acid composition varies allowing them to interact with many different antigens. It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen. Although a huge repertoire of different antibodies is generated in a single individual, the number of genes available to make these proteins is limited. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes. ## V(D)J recombination Somatic recombination of immunoglobulins, also known as V(D)J recombination, involves the generation of a unique immunoglobulin variable region. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces - known as gene segments. These segments are called variable (V), diversity (D) and joining (J) segments. V, D and J segments are found in Ig heavy chains, but only V and J segments are found in Ig light chains. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the genomes of mammals. In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different paratopes, and thus different antigen specificities. After a B cell produces a functional immunoglobulin gene during V(D)J recombination, it cannot express any other variable region (a process known as allelic exclusion) thus each B cell can produce antibodies containing only one kind of variable chain. ## Somatic hypermutation and affinity maturation Another mechanism that generates antibody diversity occurs in the mature B cell. Following activation with antigen, B cells begin to proliferate rapidly. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation (SHM). SHM results in approximately one nucleotide change per variable gene, per cell division. As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains. Somatic hypermutation serves to increase the diversity of the antibody pool and impacts the antibody’s antigen-binding affinity. Some point mutations will result in the production of antibodies that have a weaker interaction (low affinity) with their antigen than the original antibody, and some mutations will generate antibodies with a stronger interaction (high affinity). B cells that express high affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by apoptosis. Thus, B cells expressing higher affinity antibodies for will outcompete those with weaker affinities for function and survival. The process of generating antibodies with increased binding affinities is called affinity maturation. Affinity maturation occurs in mature B cells after V(D)J recombination, and is dependent on help from helper T cells. ## Class switching Isotype or class switching is a biological process occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG). The different classes of antibody, and thus effector functions, are defined by the constant (C) regions of the immunoglobulin heavy chain. Initially, naïve B cells express only cell-surface IgM and IgD with identical antigen binding regions. Each isotype is adapted for a distinct function, therefore, after activation, an antibody with a IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen. Class switching allows different daughter cells from the same activated B cell to produce antibodies of different isotypes. Only the constant region of the antibody heavy chain changes during class switching; the variable regions, and therefore antigen specificity, remain unchanged. Thus the progeny of a single B cell can produce antibodies, all specific for the same antigen, but with the ability to produce the effector function appropriate for each antigenic challenge. Class switching is triggered by cytokines; the isotype generated depends on which cytokines are present in the B cell environment. Class switching occurs in the heavy chain gene locus by a mechanism called class switch recombination (CSR). This mechanism relies on conserved nucleotide motifs, called switch (S) regions, found in DNA upstream of each constant region gene (except in the δ-chain). The DNA strand is broken by the activity of a series of enzymes at two selected S-regions. The variable domain exon is rejoined through a process called non-homologous end joining (NHEJ) to the desired constant region (γ, α or ε). This process results in an immunoglobulin gene that encodes an antibody of a different isotype. # Medical applications ## Disease diagnosis Detection of particular antibodies is a very common form of medical diagnostics, and applications such as serology depend on these methods. For example, in biochemical assays for disease diagnosis, a titer of antibodies directed against Epstein-Barr virus or Lyme disease is estimated from the blood. If those antibodies are not present, either the person is not infected, or the infection occurred a very long time ago, and the B cells generating these specific antibodies have naturally decayed. In clinical immunology, levels of individual classes of immunoglobulins are measured by nephelometry (or turbidimetry) to characterize the antibody profile of patient. Elevations in different classes of immunoglobulins are sometimes useful in determining the cause of liver damage in patients whom the diagnosis is unclear. For example, elevated IgA indicates alcoholic cirrhosis, elevated IgM indicates viral hepatitis and primary biliary cirrhosis, while IgG is elevated in viral hepatitis, autoimmune hepatitis and cirrhosis. Autoimmune disorders can often be traced to antibodies that bind the body's own epitopes; many can be detected through blood tests. Antibodies directed against red blood cell surface antigens in immune mediated hemolytic anemia are detected with the Coombs test. The Coombs test is also used for antibody screening in blood transfusion preparation and also for antibody screening in antenatal women. Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example ELISA, immunofluorescence, Western blot, immunodiffusion, and immunoelectrophoresis. ## Disease therapy "Targeted" monoclonal antibody therapy is employed to treat diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, and many forms of cancer including non-Hodgkin's lymphoma, colorectal cancer, head and neck cancer and breast cancer. Some immune deficiencies, such as X-linked agammaglobulinemia and hypogammaglobulinemia, result in partial or complete lack of antibodies. These diseases are often treated by inducing a short term form of immunity called passive immunity. Passive immunity is achieved through the transfer of ready-made antibodies in the form of human or animal serum, pooled immunoglobulin or monoclonal antibodies, into the affected individual. ## Prenatal therapy Rho(D) Immune Globulin antibodies are specific for human Rhesus D antigen, also known as Rhesus factor. These antibodies are known under several brand names, including RhoGAM. Rhesus factor is an antigen found on red blood cells; individuals that are Rhesus-positive (Rh+) have this antigen on their red blood cells and individuals that are Rhesus-negative (Rh-) do not. During normal childbirth, delivery trauma or complications during pregnancy, blood from a fetus can enter the mother's system. In the case of an Rh-incompatible mother and child, consequential blood mixing may sensitize an Rh- mother to the Rh antigen on the blood cells of the Rh+ child, putting the remainder of the pregnancy, and any subsequent pregnancies, at risk for hemolytic disease of the newborn. RhoGAM is administered as part of a prenatal treatment regimen to prevent sensitization that may occur when a Rhesus-negative mother has a Rhesus-positive fetus. Treatment of a mother with RhoGAM antibodies prior to and immediately after trauma and delivery destroys Rh antigen in the mother's system from the fetus. Importantly, this occurs before the antigen can stimulate maternal B cells to "remember" Rh antigen by generating memory B cells. Therefore, her humoral immune system will not make anti-Rh antibodies, and will not attack the Rhesus antigens of the current or subsequent baby. RhoGAM treatment prevents sensitization that can lead to Rh disease, but does not prevent or treat the underlying disease itself. # Research applications Specific antibodies are produced by injecting an antigen into a mammal, such as a mouse, rat or rabbit for small quantities of antibody, or goat, sheep, or horse for large quantities of antibody. Blood isolated from these animals contains polyclonal antibodies — multiple antibodies that bind to the same antigen — in the serum, which can now be called antiserum. Antigens are also injected into chickens for generation of polyclonal antibodies in egg yolk. To obtain antibody that is specific for a single epitope of an antigen, antibody-secreting lymphocytes are isolated from the animal and immortalized by fusing them with a cancer cell line. The fused cells are called hybridomas, and will continually grow and secrete antibody in culture. Single hybridoma cells are isolated by dilution cloning to generate cell clones that all produce the same antibody; these antibodies are called monoclonal antibodies. Generated polyclonal and monoclonal antibodies are often purified using Protein A/G or antigen-affinity chromatography. ## Use In research, purified antibodies are used in many applications. They are most commonly used to identify and locate intracellular and extracellular proteins. Antibodies are used in flow cytometry to differentiate cell types by the proteins they express; different types of cell express different combinations of cluster of differentiation molecules on their surface, and produce different intracellular and secretable proteins. They are also used in immunoprecipitation to separate proteins and anything bound to them (co-immunoprecipitation) from other molecules in a cell lysate, in Western blot analyses to identify proteins separated by electrophoresis, and in immunohistochemistry or immunofluorescence to examine protein expression in tissue sections or to locate proteins within cells with the assistance of a microscope. Proteins can also be detected and quantified with antibodies, using ELISA and ELISPOT techniques. # History The study of antibodies began in 1890 when Emil von Behring and Shibasaburo Kitasato described antibody activity against diphtheria and tetanus toxins. Behring and Kitasato put forward the theory of humoral immunity, proposing that a mediator in serum could react with a foreign antigen. Their idea prompted Paul Ehrlich to propose the side chain theory for antibody and antigen interaction in 1897, when he hypothesized that receptors (described as “side chains”) on the surface of cells could bind specifically to toxins – in a "lock-and-key" interaction – and that this binding reaction was the trigger for the production of antibodies. Other researchers believed that antibodies existed freely in the blood and, in 1904, Almroth Wright suggested that soluble antibodies coated bacteria to label them for phagocytosis and killing; a process that he named opsoninization. In the 1920s, Michael Heidelberger and Oswald Avery observed that antigens could be precipitated by antibodies and went on to show that antibodies were made of protein. The biochemical properties of antigen-antibody binding interactions were examined in more detail in the late 1930s by John Marrack. The next major advance was in the 1940s, when Linus Pauling confirmed the lock-and-key theory proposed by Ehrlich by showing that the interactions between antibodies and antigens depended more on their shape than their chemical composition. In 1948, Astrid Fagreaus discovered that B cells, in the form of plasma cells, were responsible for generating antibodies. Further work concentrated on characterizing the structures of the antibody proteins. A major advance in these structural studies was the discovery in the early 1960s by Gerald Edelman and Joseph Gally of the antibody light chain, and their realization that this protein was the same as the Bence-Jones protein described in 1845 by Henry Bence Jones. Edelman went on to discover that antibodies are composed of disulphide bond-linked heavy and light chains. Around the same time, antibody-binding (Fab) and antibody tail (Fc) regions of IgG were characterized by Rodney Porter. Together, these scientists deduced the structure and complete amino acid sequence of IgG, a feat for which they were jointly awarded the 1972 Nobel prize in Physiology or Medicine. While most of these early studies focused on IgM and IgG, other immunoglobulin isotypes were identified in the 1960s: Thomas Tomasi discovered secretory antibody (IgA) and David Rowe and John Fahey identified IgD, and IgE was identified by Kikishige Ishizaka and Teruki Ishizaka as a class of antibodies involved in allergic reactions. Genetic studies revealed the basis of the vast diversity of these antibody proteins when somatic recombination of immunoglobulin genes was identified by Susumu Tonegawa in 1976.	Antibodies Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Antibodies are Y-shaped proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. They are made of a few basic structural units called chains; each antibody has two large heavy chains and two small light chains. There are several different types of antibody heavy chain, and several different kinds of antibodies, which are grouped into different isotypes based on which heavy chain they possess. Five different antibody isotypes are known in mammals, which perform different roles, and help direct the appropriate immune response for each different type of foreign object they encounter.[1] Although the general structure of all antibodies is very similar, a small region at the tip of the protein is extremely variable, allowing millions of antibodies with slightly different tip structures to exist. Each of these variants can bind to a different target, known as an antigen.[2] This huge diversity of antibodies allows the immune system to recognize an equally wide diversity of antigens. The unique part of the antigen recognized by an antibody is called an epitope. These epitopes fit precisely with their antibody, similar to a key fitting into a lock, in a highly specific interaction that allows antibodies to identify and bind only their unique antigen in the midst of the millions of different molecules that make up an organism. Recognition of an antigen by an antibody tags it for attack by other parts of the immune system. Antibodies can also neutralize targets directly by, for example, binding to a part of a pathogen that it needs to cause an infection.[3] The large and diverse population of antibodies is generated by random combinations of a set of gene segments that encode different antigen binding sites (or paratopes), followed by random mutations in this area of the antibody gene, which create further diversity.[1][4] Antibody genes also re-organize in a process called class switching that changes the base of the heavy chain to another, creating a different isotype of the antibody that retains the antigen specific variable region. This allows a single antibody to be used by several different parts of the immune system. Antibodies occur in two forms: a soluble form secreted into the blood and tissue fluids, and a membrane-bound form attached to the surface of a B cell that is called the B cell receptor (BCR). The BCR allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation.[5] Activated B cells differentiate into either antibody generating factories called plasma cells that secrete soluble antibody, or into memory cells that survive in the body for years afterwards to allow the immune system to remember an antigen and respond faster upon future exposures.[6] Antibodies are, therefore, an essential component of the adaptive immune system that learns, adapts and remembers responses to invading pathogens. Production of antibodies is the main function of the humoral immune system.[7] # Isotypes Antibodies can come in different forms known as isotypes or classes. In mammals there are five antibody isotypes known as IgA, IgD, IgE,IgG and IgM. They are each named with an "Ig" prefix that stands for immunoglobulin, another name for antibody, and differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in the table.[10] The antibody isotype of a B cell changes during the cell's development and activation. Immature B cells, which have never been exposed to antigen, are known as naïve B cells and express only the IgM isotype in a cell surface bound form. B cells begin to express both IgM and IgD when they reach maturity - the co-expression of both these immunoglobulin isotypes renders the B cell 'mature' and ready to respond to antigen.[11] B cell activation follows engagement of the cell bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody producing cell called a plasma cell. In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane-bound form. Some daughter cells of the activated B cells undergo isotype switching, a mechanism that causes the production of antiodies to change from IgM or IgD to the other antibody isotypes, IgE, IgA or IgG, that have defined roles in the immune system. # Structure Antibodies are heavy globular plasma proteins that are also known as immunoglobulins. They have sugar chains added to some of their amino acid residues.[12] In other words, antibodies are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.[13] ## Immunoglobulin domains The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds.[10] Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or IgV, and constant or IgC) according to their size and function.[14] They possess a characteristic immunoglobulin fold in which two beta sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids. ## Heavy chain There are five types of mammalian Ig heavy chain denoted by the Greek letters: α, δ, ε, γ, and μ.[2] The type of heavy chain present defines the class of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.[3] Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids, while μ and ε have approximately 550 amino acids.[2] Each heavy chain has two regions, the constant region and the variable region. The constant region is identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem (in a line) Ig domains, and a hinge region for added flexibility;[10] heavy chains μ and ε have a constant region composed of four immunoglobulin domains.[2] The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. ## Light chain In mammals there are only two types of light chain, which are called lambda (λ) and kappa (κ).[2] A light chain has two successive domains: one constant domain and one variable domain. The approximate length of a light chain is 211 to 217 amino acids.[2] Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals. Other types of light chains, such as the iota (ι) chain, are found in lower vertebrates like Chondrichthyes and Teleostei. ## Fab and Fc Regions Some parts of an antibody have unique functions. The tip of the Y, for example, contains the site that binds antigen and, therefore, recognizes specific foreign objects. This region of the antibody is called the Fab (fragment, antigen binding) region. It is composed of one constant and one variable domain from each heavy and light chain of the antibody.[15] The paratope is shaped at the amino terminal end of the antibody monomer by the variable domains from the heavy and light chains. The base of the Y plays a role in modulating immune cell activity. This region is called the Fc (Fragment, crystallizable) region, and is composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody.[2] By binding to specific proteins the Fc region ensures that each antibody generates an appropriate immune response for a given antigen.[16] The Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins. By doing this, it mediates different physiological effects including opsonization, cell lysis, and degranulation of mast cells, basophils and eosinophils.[10][17] # Function Since antibodies exist freely in the bloodstream, they are said to be part of the humoral immune system. Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen, a virus hull protein fragment, for example. Antibodies contribute to immunity in three main ways: they can prevent pathogens from entering or damaging cells by binding to them; they can stimulate removal of a pathogen by macrophages and other cells by coating the pathogen; and they can trigger direct pathogen destruction by stimulating other immune responses such as the complement pathway.[18] ## Activation of complement Antibodies that bind to surface antigens on, for example a bacterium, attract the first component of the complement cascade with their Fc region and initiate activation of the "classical" complement system.[18] This results in the killing of bacteria in two ways.[7] First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization; these phagocytes are attracted by certain complement molecules generated in the complement cascade. Secondly, some complement system components form a membrane attack complex to assist antibodies to kill the bacterium directly.[19] ## Activation of effector cells To combat pathogens that replicate outside cells antibodies bind to pathogens to link them together, causing them to agglutinate. Since an antibody possesses at least two paratopes it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region.[7] Those cells which recognize coated pathogens have Fc receptors which, as the name suggests, interacts with the Fc region of IgA, IgG, and IgE antibodies. The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell; phagocytes will phagocytose, mast cells and neutrophils will degranulate, natural killer cells will release cytokines and cytotoxic molecules; that will ultimately result in destruction of the invading microbe. The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens.[2] # Immunoglobulin diversity Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies; their amino acid composition varies allowing them to interact with many different antigens.[20] It has been estimated that humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen.[21] Although a huge repertoire of different antibodies is generated in a single individual, the number of genes available to make these proteins is limited. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes.[22] ## V(D)J recombination Somatic recombination of immunoglobulins, also known as V(D)J recombination, involves the generation of a unique immunoglobulin variable region. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces - known as gene segments. These segments are called variable (V), diversity (D) and joining (J) segments.[22] V, D and J segments are found in Ig heavy chains, but only V and J segments are found in Ig light chains. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the genomes of mammals. In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different paratopes, and thus different antigen specificities.[1] After a B cell produces a functional immunoglobulin gene during V(D)J recombination, it cannot express any other variable region (a process known as allelic exclusion) thus each B cell can produce antibodies containing only one kind of variable chain.[23][2] ## Somatic hypermutation and affinity maturation Another mechanism that generates antibody diversity occurs in the mature B cell. Following activation with antigen, B cells begin to proliferate rapidly. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation (SHM). SHM results in approximately one nucleotide change per variable gene, per cell division.[4] As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains. Somatic hypermutation serves to increase the diversity of the antibody pool and impacts the antibody’s antigen-binding affinity.[24] Some point mutations will result in the production of antibodies that have a weaker interaction (low affinity) with their antigen than the original antibody, and some mutations will generate antibodies with a stronger interaction (high affinity).[25] B cells that express high affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by apoptosis.[25] Thus, B cells expressing higher affinity antibodies for will outcompete those with weaker affinities for function and survival. The process of generating antibodies with increased binding affinities is called affinity maturation. Affinity maturation occurs in mature B cells after V(D)J recombination, and is dependent on help from helper T cells.[26] ## Class switching Isotype or class switching is a biological process occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG).[1] The different classes of antibody, and thus effector functions, are defined by the constant (C) regions of the immunoglobulin heavy chain. Initially, naïve B cells express only cell-surface IgM and IgD with identical antigen binding regions. Each isotype is adapted for a distinct function, therefore, after activation, an antibody with a IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen. Class switching allows different daughter cells from the same activated B cell to produce antibodies of different isotypes. Only the constant region of the antibody heavy chain changes during class switching; the variable regions, and therefore antigen specificity, remain unchanged. Thus the progeny of a single B cell can produce antibodies, all specific for the same antigen, but with the ability to produce the effector function appropriate for each antigenic challenge. Class switching is triggered by cytokines; the isotype generated depends on which cytokines are present in the B cell environment.[27] Class switching occurs in the heavy chain gene locus by a mechanism called class switch recombination (CSR). This mechanism relies on conserved nucleotide motifs, called switch (S) regions, found in DNA upstream of each constant region gene (except in the δ-chain). The DNA strand is broken by the activity of a series of enzymes at two selected S-regions.[28][29] The variable domain exon is rejoined through a process called non-homologous end joining (NHEJ) to the desired constant region (γ, α or ε). This process results in an immunoglobulin gene that encodes an antibody of a different isotype.[30] # Medical applications ## Disease diagnosis Detection of particular antibodies is a very common form of medical diagnostics, and applications such as serology depend on these methods.[31] For example, in biochemical assays for disease diagnosis,[32] a titer of antibodies directed against Epstein-Barr virus or Lyme disease is estimated from the blood. If those antibodies are not present, either the person is not infected, or the infection occurred a very long time ago, and the B cells generating these specific antibodies have naturally decayed. In clinical immunology, levels of individual classes of immunoglobulins are measured by nephelometry (or turbidimetry) to characterize the antibody profile of patient.[33] Elevations in different classes of immunoglobulins are sometimes useful in determining the cause of liver damage in patients whom the diagnosis is unclear.[3] For example, elevated IgA indicates alcoholic cirrhosis, elevated IgM indicates viral hepatitis and primary biliary cirrhosis, while IgG is elevated in viral hepatitis, autoimmune hepatitis and cirrhosis. Autoimmune disorders can often be traced to antibodies that bind the body's own epitopes; many can be detected through blood tests. Antibodies directed against red blood cell surface antigens in immune mediated hemolytic anemia are detected with the Coombs test.[34] The Coombs test is also used for antibody screening in blood transfusion preparation and also for antibody screening in antenatal women.[34] Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example ELISA, immunofluorescence, Western blot, immunodiffusion, and immunoelectrophoresis. ## Disease therapy "Targeted" monoclonal antibody therapy is employed to treat diseases such as rheumatoid arthritis,[35] multiple sclerosis,[36] psoriasis,[37] and many forms of cancer including non-Hodgkin's lymphoma,[38] colorectal cancer, head and neck cancer and breast cancer.[39] Some immune deficiencies, such as X-linked agammaglobulinemia and hypogammaglobulinemia, result in partial or complete lack of antibodies.[40] These diseases are often treated by inducing a short term form of immunity called passive immunity. Passive immunity is achieved through the transfer of ready-made antibodies in the form of human or animal serum, pooled immunoglobulin or monoclonal antibodies, into the affected individual.[41] ## Prenatal therapy Rho(D) Immune Globulin antibodies are specific for human Rhesus D antigen, also known as Rhesus factor.[42] These antibodies are known under several brand names, including RhoGAM. Rhesus factor is an antigen found on red blood cells; individuals that are Rhesus-positive (Rh+) have this antigen on their red blood cells and individuals that are Rhesus-negative (Rh-) do not. During normal childbirth, delivery trauma or complications during pregnancy, blood from a fetus can enter the mother's system. In the case of an Rh-incompatible mother and child, consequential blood mixing may sensitize an Rh- mother to the Rh antigen on the blood cells of the Rh+ child, putting the remainder of the pregnancy, and any subsequent pregnancies, at risk for hemolytic disease of the newborn.[43] RhoGAM is administered as part of a prenatal treatment regimen to prevent sensitization that may occur when a Rhesus-negative mother has a Rhesus-positive fetus. Treatment of a mother with RhoGAM antibodies prior to and immediately after trauma and delivery destroys Rh antigen in the mother's system from the fetus. Importantly, this occurs before the antigen can stimulate maternal B cells to "remember" Rh antigen by generating memory B cells. Therefore, her humoral immune system will not make anti-Rh antibodies, and will not attack the Rhesus antigens of the current or subsequent baby. RhoGAM treatment prevents sensitization that can lead to Rh disease, but does not prevent or treat the underlying disease itself.[42] # Research applications Specific antibodies are produced by injecting an antigen into a mammal, such as a mouse, rat or rabbit for small quantities of antibody, or goat, sheep, or horse for large quantities of antibody. Blood isolated from these animals contains polyclonal antibodies — multiple antibodies that bind to the same antigen — in the serum, which can now be called antiserum. Antigens are also injected into chickens for generation of polyclonal antibodies in egg yolk.[44] To obtain antibody that is specific for a single epitope of an antigen, antibody-secreting lymphocytes are isolated from the animal and immortalized by fusing them with a cancer cell line. The fused cells are called hybridomas, and will continually grow and secrete antibody in culture. Single hybridoma cells are isolated by dilution cloning to generate cell clones that all produce the same antibody; these antibodies are called monoclonal antibodies.[45] Generated polyclonal and monoclonal antibodies are often purified using Protein A/G or antigen-affinity chromatography.[46] ## Use In research, purified antibodies are used in many applications. They are most commonly used to identify and locate intracellular and extracellular proteins. Antibodies are used in flow cytometry to differentiate cell types by the proteins they express; different types of cell express different combinations of cluster of differentiation molecules on their surface, and produce different intracellular and secretable proteins.[47] They are also used in immunoprecipitation to separate proteins and anything bound to them (co-immunoprecipitation) from other molecules in a cell lysate,[48] in Western blot analyses to identify proteins separated by electrophoresis,[49] and in immunohistochemistry or immunofluorescence to examine protein expression in tissue sections or to locate proteins within cells with the assistance of a microscope.[50][47] Proteins can also be detected and quantified with antibodies, using ELISA and ELISPOT techniques.[51][52] # History The study of antibodies began in 1890 when Emil von Behring and Shibasaburo Kitasato described antibody activity against diphtheria and tetanus toxins. Behring and Kitasato put forward the theory of humoral immunity, proposing that a mediator in serum could react with a foreign antigen.[53][54] Their idea prompted Paul Ehrlich to propose the side chain theory for antibody and antigen interaction in 1897, when he hypothesized that receptors (described as “side chains”) on the surface of cells could bind specifically to toxins – in a "lock-and-key" interaction – and that this binding reaction was the trigger for the production of antibodies.[55] Other researchers believed that antibodies existed freely in the blood and, in 1904, Almroth Wright suggested that soluble antibodies coated bacteria to label them for phagocytosis and killing; a process that he named opsoninization.[56] In the 1920s, Michael Heidelberger and Oswald Avery observed that antigens could be precipitated by antibodies and went on to show that antibodies were made of protein.[57] The biochemical properties of antigen-antibody binding interactions were examined in more detail in the late 1930s by John Marrack.[58] The next major advance was in the 1940s, when Linus Pauling confirmed the lock-and-key theory proposed by Ehrlich by showing that the interactions between antibodies and antigens depended more on their shape than their chemical composition.[59] In 1948, Astrid Fagreaus discovered that B cells, in the form of plasma cells, were responsible for generating antibodies.[60] Further work concentrated on characterizing the structures of the antibody proteins. A major advance in these structural studies was the discovery in the early 1960s by Gerald Edelman and Joseph Gally of the antibody light chain,[61] and their realization that this protein was the same as the Bence-Jones protein described in 1845 by Henry Bence Jones.[62] Edelman went on to discover that antibodies are composed of disulphide bond-linked heavy and light chains. Around the same time, antibody-binding (Fab) and antibody tail (Fc) regions of IgG were characterized by Rodney Porter.[63] Together, these scientists deduced the structure and complete amino acid sequence of IgG, a feat for which they were jointly awarded the 1972 Nobel prize in Physiology or Medicine.[63] While most of these early studies focused on IgM and IgG, other immunoglobulin isotypes were identified in the 1960s: Thomas Tomasi discovered secretory antibody (IgA) [64] and David Rowe and John Fahey identified IgD,[65] and IgE was identified by Kikishige Ishizaka and Teruki Ishizaka as a class of antibodies involved in allergic reactions.[66] Genetic studies revealed the basis of the vast diversity of these antibody proteins when somatic recombination of immunoglobulin genes was identified by Susumu Tonegawa in 1976.[67]	https://www.wikidoc.org/index.php/Antibodies
deb77329b50c5b97f83a7c85a7d53d389c813d2a	wikidoc	Antifreeze	Antifreeze # Overview Antifreeze is used in internal combustion engines, and for many other heat transfer applications, such as electronics cooling and chillers for HVAC. Compounds are added to water to reduce the freezing point of the mixture to below the lowest temperature that the system is likely to be exposed to, and to inhibit corrosion in cooling systems which often contain a range of electrochemically incompatible metals (aluminum, cast iron, copper, lead solder, etc.). The term "colligative agent" is to be preferred as, in warm climates, the benefit of these compounds is to increase the boiling point of the coolant, which should then be more properly referred to as "anti-boil", and as anti-freeze decreases and increases both properties, respectively, "colligative agent" more accurately describes the liquid. The term "engine coolant" is widely used in industry. # Agents ## Methanol Methanol, also known as methyl alcohol, carbinol, wood alcohol, wood naphtha or wood spirits, is a chemical compound with chemical formula CH3OH (often abbreviated MeOH). It is the simplest alcohol, and is a light, volatile, colourless, flammable, poisonous liquid with a distinctive odor that is somewhat milder and sweeter than ethanol (ethyl alcohol). At room temperature it is a polar liquid and is used as an antifreeze, solvent, fuel, and as a denaturant for ethyl alcohol. ## Ethylene glycol Ethylene glycol solutions became available in 1926 and were marketed as "permanent antifreeze", since the higher boiling points provided advantages for summertime use as well as during cold weather. They are still used today. Ethylene glycol antifreezes are poisonous and should be kept away from any person or animal (children and especially cats) that might be tempted by its sweet taste. They form calcium oxalate crystals in the kidneys and can cause acute renal failure and death. All spills should be cleaned, or else an area in which it may be present should be kept inaccessible. Should ingestion of antifreeze occur, ethanol (alcoholic beverages) can be administered until proper treatment can be started in order to slow the conversion of methanol to formaldehyde and formic acid which are the substances responsible for methanol's toxicity. In practice, ethanol can be administered intravenously by doctors to counter ethylene glycol and methanol poisoning, but now that another antidote is available (fomepizole), its popularity for this application is greatly in decline. In order to prevent ingestion, bittering agent (denatonium benzoate) is usually added to engine coolant to make it taste unpleasant. In the United States, there is legislation before Congress (H.R.2567/S.1110) that would make the use of a bittering agent mandatory. ## Propylene glycol Propylene glycol, on the other hand, is considerably less toxic and may be labeled as "non-toxic antifreeze". It is used as antifreeze where ethylene glycol would be inappropriate, such as in food-processing systems or in water pipes in homes, as well as numerous other settings. It is also used in food, medicines, and cosmetics, often as a binding agent. Propylene glycol is "generally recognized as safe" by the Food and Drug Administration (FDA) for use in food. However, propylene glycol-based antifreeze should not be considered safe for consumption. In the event of accidental ingestion, emergency medical services should be contacted immediately. Propylene Glycol oxidizes when exposed to air and heat. When this occurs, organic acids are formed viz. Glycolic acid, Glyoxalic acid, Formic acid, Carbonic acid & Oxalic acid. If not properly inhibited, this fluid can be very corrosive. Protodin is added to Propylene Glycol to act as a buffer, preventing low pH attack on the system metals. It forms a protective skin inside the tank and pipelines which helps to prevent acid attack that cause corrosion. Beside cooling system breakdown, biological fouling also occurs. Once bacterial slime starts the corrosion rate of the system increases. In system where a glycol solution is maintained on a continuous basis, regular monitoring of freeze protection, pH, specific gravity, inhibitor level, color and biological contamination should be checked on routine basis. Propylene glycol should be replaced when it turns reddish in color. # Other developments Most commercial antifreeze formulations include corrosion inhibiting compounds, and a colored dye (commonly a green, red or blue fluorescent) to aid in identification. A 1:1 dilution with water is usually used, resulting in a freezing point of approximately −40 °C. In warmer areas weaker dilutions are used. Glycol antifreeze solutions should generally be replaced with fresh mixture every two years. In the 1980s, inventor Jack Evans discovered the advantages of using a waterless coolant. His final formulation is a mixture propylene glycol. This coolant has a high boiling point of 188 °C (370 °F) and is not corrosive, solving many of water's problems including freezing. ## Organic acid technology Certain cars are built with Organic Acid Technology (OAT) antifreeze (e.g., DEX-COOL ), which is claimed to have an extended service life of five years or 240,000 km (150,000 miles). According to the DEX-COOL manufacturer, "mixing a 'green' coolant with DEX-COOL reduces the batch’s change interval to 2 years or 30,000 miles, but will otherwise cause no damage to the engine." DEX-COOL specifically has caused controversy. It is casually linked with intake manifold gasket failures in GM's 3.1L and 3.4L and with other failures in 4.3L engines. Class action lawsuits were registered in several states, and in Canada, to address some of these claims. The first of these to reach a decision was in Missouri where a settlement was announced early in December, 2007. Late in March 2008, GM agreed to compensate complainants in the remaining 49 states. Typically OAT antifreeze contains a red or pink dye to differentiate it from the conventional glycol-based coolants (blue or green). Some of the newer OAT coolants claim to be compatible with all types of OAT and glycol-based coolants; these are typically green or yellow in color. ## Effects on the human body Anti-freeze turns to acid in the body and drinking just a small amount could be fatal. Nerve endings and blood vessels would be destroyed and tissue in the kidneys, brain and liver severely affected. Blindness and deafness can result and the nervous system comes under attack, leading to violent spasms in the limbs. ## Famous Poisoning Cases In a case in April 2005, Kate Knight of Stoke-On-Trent, Staffordshire, carried out a plan to poison and kill her husband Lee Knight, after learning she would gain over UK£100,000 from his employers JCB after his death. It is believed her motive for carrying out such an act was to pay off debts of thousands of pounds. Mr Knight had his food contaminated by antifreeze and subsequently came close to death. Mr Knight remained in a coma for 16 weeks and eventually managed to pull through. Despite this, he was left with brain damage, kidney failure, blindness, and deafness. Kate Knight was found guilty of his attempted murder and was jailed for 30 years in February 2008. Mr Knight has since spoken openly about his relationship with her and how he is coping today. His neighbour said he is not the same person but has a good sense of humour, recalling how he laughed about waking up well on frosty mornings. Others close to him have said he is being 'strong' and 'doing well'.	Antifreeze Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Antifreeze is used in internal combustion engines, and for many other heat transfer applications, such as electronics cooling and chillers for HVAC. Compounds are added to water to reduce the freezing point of the mixture to below the lowest temperature that the system is likely to be exposed to, and to inhibit corrosion in cooling systems which often contain a range of electrochemically incompatible metals (aluminum, cast iron, copper, lead solder, etc.). The term "colligative agent" is to be preferred as, in warm climates, the benefit of these compounds is to increase the boiling point of the coolant, which should then be more properly referred to as "anti-boil", and as anti-freeze decreases and increases both properties, respectively, "colligative agent" more accurately describes the liquid. The term "engine coolant" is widely used in industry. # Agents ## Methanol Methanol, also known as methyl alcohol, carbinol, wood alcohol, wood naphtha or wood spirits, is a chemical compound with chemical formula CH3OH (often abbreviated MeOH). It is the simplest alcohol, and is a light, volatile, colourless, flammable, poisonous liquid with a distinctive odor that is somewhat milder and sweeter than ethanol (ethyl alcohol). At room temperature it is a polar liquid and is used as an antifreeze, solvent, fuel, and as a denaturant for ethyl alcohol. ## Ethylene glycol Ethylene glycol solutions became available in 1926 and were marketed as "permanent antifreeze", since the higher boiling points provided advantages for summertime use as well as during cold weather. They are still used today. Ethylene glycol antifreezes are poisonous and should be kept away from any person or animal (children and especially cats) that might be tempted by its sweet taste. They form calcium oxalate crystals in the kidneys and can cause acute renal failure and death. All spills should be cleaned, or else an area in which it may be present should be kept inaccessible. Should ingestion of antifreeze occur, ethanol (alcoholic beverages) can be administered until proper treatment can be started in order to slow the conversion of methanol to formaldehyde and formic acid which are the substances responsible for methanol's toxicity. In practice, ethanol can be administered intravenously by doctors to counter ethylene glycol and methanol poisoning, but now that another antidote is available (fomepizole), its popularity for this application is greatly in decline. [1] In order to prevent ingestion, bittering agent (denatonium benzoate) is usually added to engine coolant to make it taste unpleasant. In the United States, there is legislation before Congress (H.R.2567/S.1110) that would make the use of a bittering agent mandatory. ## Propylene glycol Propylene glycol, on the other hand, is considerably less toxic and may be labeled as "non-toxic antifreeze". It is used as antifreeze where ethylene glycol would be inappropriate, such as in food-processing systems or in water pipes in homes, as well as numerous other settings. It is also used in food, medicines, and cosmetics, often as a binding agent. Propylene glycol is "generally recognized as safe" by the Food and Drug Administration (FDA) for use in food. However, propylene glycol-based antifreeze should not be considered safe for consumption. In the event of accidental ingestion, emergency medical services should be contacted immediately. Propylene Glycol oxidizes when exposed to air and heat. When this occurs, organic acids are formed viz. Glycolic acid, Glyoxalic acid, Formic acid, Carbonic acid & Oxalic acid. If not properly inhibited, this fluid can be very corrosive. Protodin is added to Propylene Glycol to act as a buffer, preventing low pH attack on the system metals. It forms a protective skin inside the tank and pipelines which helps to prevent acid attack that cause corrosion. Beside cooling system breakdown, biological fouling also occurs. Once bacterial slime starts the corrosion rate of the system increases. In system where a glycol solution is maintained on a continuous basis, regular monitoring of freeze protection, pH, specific gravity, inhibitor level, color and biological contamination should be checked on routine basis. Propylene glycol should be replaced when it turns reddish in color. # Other developments Most commercial antifreeze formulations include corrosion inhibiting compounds, and a colored dye (commonly a green, red or blue fluorescent) to aid in identification. A 1:1 dilution with water is usually used, resulting in a freezing point of approximately −40 °C. In warmer areas weaker dilutions are used. Glycol antifreeze solutions should generally be replaced with fresh mixture every two years. In the 1980s, inventor Jack Evans discovered the advantages of using a waterless coolant. His final formulation is a mixture propylene glycol. This coolant has a high boiling point of 188 °C (370 °F) and is not corrosive, solving many of water's problems including freezing. [2] ## Organic acid technology Certain cars are built with Organic Acid Technology (OAT) antifreeze (e.g., DEX-COOL [2]), which is claimed to have an extended service life of five years or 240,000 km (150,000 miles)[3]. According to the DEX-COOL manufacturer, "mixing a 'green' coolant with DEX-COOL reduces the batch’s change interval to 2 years or 30,000 miles, but will otherwise cause no damage to the engine."[4] DEX-COOL specifically has caused controversy. [5] It is casually linked with intake manifold gasket failures in GM's 3.1L and 3.4L and with other failures in 4.3L engines. Class action lawsuits were registered in several states, and in Canada,[6] to address some of these claims. The first of these to reach a decision was in Missouri where a settlement was announced early in December, 2007. [7] Late in March 2008, GM agreed to compensate complainants in the remaining 49 states.[8] Typically OAT antifreeze contains a red or pink dye to differentiate it from the conventional glycol-based coolants (blue or green). Some of the newer OAT coolants claim to be compatible with all types of OAT and glycol-based coolants; these are typically green or yellow in color. ## Effects on the human body Anti-freeze turns to acid in the body and drinking just a small amount could be fatal. Nerve endings and blood vessels would be destroyed and tissue in the kidneys, brain and liver severely affected. Blindness and deafness can result and the nervous system comes under attack, leading to violent spasms in the limbs. ## Famous Poisoning Cases In a case in April 2005, Kate Knight of Stoke-On-Trent, Staffordshire, carried out a plan to poison and kill her husband Lee Knight, after learning she would gain over UK£100,000 from his employers JCB after his death. It is believed her motive for carrying out such an act was to pay off debts of thousands of pounds. Mr Knight had his food contaminated by antifreeze and subsequently came close to death. Mr Knight remained in a coma for 16 weeks and eventually managed to pull through. Despite this, he was left with brain damage, kidney failure, blindness, and deafness. Kate Knight was found guilty of his attempted murder and was jailed for 30 years in February 2008. Mr Knight has since spoken openly about his relationship with her and how he is coping today. His neighbour said he is not the same person but has a good sense of humour, recalling how he laughed about waking up well on frosty mornings. Others close to him have said he is being 'strong' and 'doing well'.	https://www.wikidoc.org/index.php/Antifreeze
111f61a8c89c9404c209497bec2a855433b8b58d	wikidoc	Antiproton	Antiproton The antiproton (Template:SubatomicParticle, pronounced p-bar) is the antiparticle of the proton. Antiprotons are stable, but they are typically short-lived since any collision with a proton will cause both particles to be annihilated in a burst of energy. It was discovered in 1955 by University of California, Berkeley physicists Emilio Segrè and Owen Chamberlain, for which they were awarded the 1959 Nobel Prize in Physics. An antiproton consists of two anti-up quarks and one anti-down quark (Template:SubatomicParticleTemplate:SubatomicParticleTemplate:SubatomicParticle). Their formation requires energy equivalent to a temperature of 10 trillion K (1013 K), and Big Bangs aside, this does not tend to happen naturally. However, at CERN, protons are accelerated in the Proton Synchrotron (PS) to an energy of 26 GeV, and then smashed into an iridium rod. The protons bounce off the iridium nuclei with enough energy for matter to be created. A range of particles and antiparticles are formed, and the antiprotons are separated off using magnets in vacuum. In mid-June 2006, CERN succeeded in determining the mass of the antiproton, which they measured at 7003183615367400000♠1836.153674(5) times more massive than an electron. This is exactly the same as the mass of a "regular" proton, necessitating further research into the nature of difference between matter and anti-matter, in order to explain how our universe survived the Big Bang and why so little remains of antimatter today in our solar system. # Occurrence in nature Antiprotons have been detected in cosmic rays for over 25 years, first by balloon-borne experiments and more recently by satellite-based detectors. The standard picture for their presence in cosmic rays is that they are produced in collisions of cosmic ray protons with nuclei in the interstellar medium, via the reaction: The secondary antiprotons (Template:SubatomicParticle) then propagate through the galaxy, confined by the galactic magnetic fields. Their energy spectrum is modified by collisions with other atoms in the interstellar medium, and antiprotons can also be lost by "leaking out" of the galaxy. The antiproton cosmic ray energy spectrum is now measured reliably and is consistent with this standard picture of antiproton production by cosmic ray collisions. This sets upper limits on the number of antiprotons that could be produced in exotic ways, such as from annihilation of supersymmetric dark matter particles in the galaxy or from the evaporation of primordial black holes. This also provides a lower limit on the antiproton lifetime of about 1-10 million years. Since the galactic storage time of antiprotons is about 10 million years, an intrinsic decay lifetime would modify the galactic residence time and distort the spectrum of cosmic ray antiprotons. This is significantly more stringent than the best laboratory measurements of the antiproton lifetime: - LEAR collaboration at CERN: 7006252460800000000♠0.08 year - Antihydrogen Penning trap of Gabrielse et al: 7006883612800000000♠0.28 year - APEX collaboration at Fermilab: 7012157788000000000♠50000 years for Template:SubatomicParticle → Template:SubatomicParticle + X and 7012946728000000000♠300000 years for Template:SubatomicParticle → Template:SubatomicParticle + Template:SubatomicParticle The properties of the antiproton are predicted by CPT symmetry to be exactly related to those of the proton. In particular, CPT symmetry predicts the mass and lifetime of the antiproton to be the same as those of the proton, and the electric charge and magnetic moment of the antiproton to be opposite in sign and equal in magnitude to those of the proton. CPT symmetry is a basic consequence of quantum field theory and no violations of it have ever been detected. ## List of recent antiproton cosmic ray detection experiments - BESS: balloon-borne experiment, flown in 1993, 1995, and 1997. - CAPRICE: balloon-borne experiment, flown in 1994. - HEAT: balloon-borne experiment, flown in 2000. - AMS: space-based experiment, prototype flown on the space shuttle in 1998, intended for the International Space Station but not yet launched. - PAMELA: satellite experiment to detect cosmic rays and antimatter from space, launched June 2006. # Uses Antiprotons are routinely produced at Fermilab for collider physics operations in the Tevatron, where they are collided with protons. The use of antiprotons allows for a higher average energy of collisions between quarks and antiquarks than would be possible in proton-proton collisions. This is because the valence quarks in the proton, and the valence antiquarks in the antiproton, tend to carry the largest fraction of the proton or antiproton's momentum.	Antiproton The antiproton (Template:SubatomicParticle, pronounced p-bar) is the antiparticle of the proton. Antiprotons are stable, but they are typically short-lived since any collision with a proton will cause both particles to be annihilated in a burst of energy. It was discovered in 1955 by University of California, Berkeley physicists Emilio Segrè and Owen Chamberlain, for which they were awarded the 1959 Nobel Prize in Physics. An antiproton consists of two anti-up quarks and one anti-down quark (Template:SubatomicParticleTemplate:SubatomicParticleTemplate:SubatomicParticle). Template:Antimatter Their formation requires energy equivalent to a temperature of 10 trillion K (1013 K), and Big Bangs aside, this does not tend to happen naturally. However, at CERN, protons are accelerated in the Proton Synchrotron (PS) to an energy of 26 GeV, and then smashed into an iridium rod. The protons bounce off the iridium nuclei with enough energy for matter to be created. A range of particles and antiparticles are formed, and the antiprotons are separated off using magnets in vacuum. In mid-June 2006, CERN succeeded in determining the mass of the antiproton, which they measured at 7003183615367400000♠1836.153674(5) times more massive than an electron. This is exactly the same as the mass of a "regular" proton, necessitating further research into the nature of difference between matter and anti-matter, in order to explain how our universe survived the Big Bang and why so little remains of antimatter today in our solar system.[citation needed] # Occurrence in nature Antiprotons have been detected in cosmic rays for over 25 years, first by balloon-borne experiments and more recently by satellite-based detectors. The standard picture for their presence in cosmic rays is that they are produced in collisions of cosmic ray protons with nuclei in the interstellar medium, via the reaction: Template:SubatomicParticle A → Template:SubatomicParticle Template:SubatomicParticle Template:SubatomicParticle A The secondary antiprotons (Template:SubatomicParticle) then propagate through the galaxy, confined by the galactic magnetic fields. Their energy spectrum is modified by collisions with other atoms in the interstellar medium, and antiprotons can also be lost by "leaking out" of the galaxy. The antiproton cosmic ray energy spectrum is now measured reliably and is consistent with this standard picture of antiproton production by cosmic ray collisions.[1] This sets upper limits on the number of antiprotons that could be produced in exotic ways, such as from annihilation of supersymmetric dark matter particles in the galaxy or from the evaporation of primordial black holes. This also provides a lower limit on the antiproton lifetime of about 1-10 million years. Since the galactic storage time of antiprotons is about 10 million years, an intrinsic decay lifetime would modify the galactic residence time and distort the spectrum of cosmic ray antiprotons. This is significantly more stringent than the best laboratory measurements of the antiproton lifetime: - LEAR collaboration at CERN: 7006252460800000000♠0.08 year - Antihydrogen Penning trap of Gabrielse et al: 7006883612800000000♠0.28 year [2] - APEX collaboration at Fermilab: 7012157788000000000♠50000 years for Template:SubatomicParticle → Template:SubatomicParticle + X and 7012946728000000000♠300000 years for Template:SubatomicParticle → Template:SubatomicParticle + Template:SubatomicParticle The properties of the antiproton are predicted by CPT symmetry to be exactly related to those of the proton. In particular, CPT symmetry predicts the mass and lifetime of the antiproton to be the same as those of the proton, and the electric charge and magnetic moment of the antiproton to be opposite in sign and equal in magnitude to those of the proton. CPT symmetry is a basic consequence of quantum field theory and no violations of it have ever been detected. ## List of recent antiproton cosmic ray detection experiments - BESS: balloon-borne experiment, flown in 1993, 1995, and 1997. - CAPRICE: balloon-borne experiment, flown in 1994.[3] - HEAT: balloon-borne experiment, flown in 2000. - AMS: space-based experiment, prototype flown on the space shuttle in 1998, intended for the International Space Station but not yet launched. - PAMELA: satellite experiment to detect cosmic rays and antimatter from space, launched June 2006. # Uses Antiprotons are routinely produced at Fermilab for collider physics operations in the Tevatron, where they are collided with protons. The use of antiprotons allows for a higher average energy of collisions between quarks and antiquarks than would be possible in proton-proton collisions. This is because the valence quarks in the proton, and the valence antiquarks in the antiproton, tend to carry the largest fraction of the proton or antiproton's momentum.	https://www.wikidoc.org/index.php/Antiproton
b8458dd1831bc3a574d49960f0a90764d6a926a2	wikidoc	Omeprazole	Omeprazole # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Omeprazole is a proton pump inhibitor that is FDA approved for the {{{indicationType}}} of duodenal ulcer, gastric ulcer, gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis and pathological hypersecretory conditions. Common adverse reactions include headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Short-Term Treatment of Active Duodenal Ulcer - The recommended adult oral dose of omeprazole delayed-release capsule USP is 20 mg once daily. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. - H. pylori Eradication for the Reduction of the Risk of Duodenal Ulcer Recurrence - Triple Therapy (omeprazole/clarithromycin/amoxicillin) The recommended adult oral regimen is omeprazole delayed-release capsule USP 20 mg plus clarithromycin 500 mg plus amoxicillin 1000 mg each given twice daily for 10 days. In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole delayed-release capsule USP 20 mg once daily is recommended for ulcer healing and symptom relief. - The recommended adult oral regimen is omeprazole delayed-release capsule USP 20 mg plus clarithromycin 500 mg plus amoxicillin 1000 mg each given twice daily for 10 days. In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole delayed-release capsule USP 20 mg once daily is recommended for ulcer healing and symptom relief. - Dual Therapy (omeprazole/clarithromycin) The recommended adult oral regimen is omeprazole delayed-release capsule USP 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days. In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of omeprazole delayed-release capsule USP 20 mg once daily is recommended for ulcer healing and symptom relief. - The recommended adult oral regimen is omeprazole delayed-release capsule USP 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days. In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of omeprazole delayed-release capsule USP 20 mg once daily is recommended for ulcer healing and symptom relief. - Omeprazole delayed-release capsules USP are indicated for short-term treatment (4 to 8 weeks) of active benign gastric ulcer in adults. - The recommended adult oral dose is 40 mg once daily for 4 to 8 weeks. - Symptomatic GERD - Omeprazole delayed-release capsules USP are indicated for the treatment of heartburn and other symptoms associated with GERD in adults. - The recommended adult oral dose for the treatment of patients with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4 weeks. - Erosive Esophagitis - Omeprazole delayed-release capsules USP are indicated for the short-term treatment (4 to 8 weeks) of erosive esophagitis that has been diagnosed by endoscopy in adults. - The efficacy of omeprazole delayed-release capsules USP used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of erosive esophagitis or GERD symptoms (eg, heartburn), additional 4 to 8 week courses of omeprazole may be considered. - The recommended adult oral dose for the treatment of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4 to 8 weeks. - Omeprazole delayed-release capsules USP are indicated to maintain healing of erosive esophagitis in adults. - Controlled studies do not extend beyond 12 months. - The recommended adult oral dose is 20 mg daily. - Omeprazole delayed-release capsules USP are indicated for the long-term treatment of pathological hypersecretory conditions (eg, Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) in adults. - The dosage of omeprazole delayed-release capsule USP in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 120 mg three times daily have been administered. Daily dosages of greater than 80 mg should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have been treated continuously with omeprazole delayed-release capsule USP for more than 5 years. ## Off-Label Use and Dosage (Adult) ### Non–Guideline-Supported Use - Dosing Information - Omeprazole dosing was 40 milligrams. - Dosing Information - Omeprazole 20 mg once a day. - Dosing Information - Omeprazole (20 milligrams (mg) daily) remained in remission throughout the 6-month. - Dosing Information - Omeprazole 20 milligrams once daily for 6 months. - Dosing Information - Omeprazole 20 to 40 mg/day. - Dosing Information - 2-week course of omeprazole 40 milligrams daily combined with either amoxicillin (minimum dose of 2 grams daily) or clarithromycin (1 gram daily). - Dosing Information - Omeprazole (40 milligrams (mg) in the morning and 20 mg in the evening) for 7 days. - Dosing Information - Omeprazole 80 milligrams (mg) intravenous (IV) bolus, followed by 8 mg per hour IV continuous infusion. - Dosing Information - Omeprazole 40 milligrams (mg). - Dosing Information - Omeprazole 20 milligrams twice daily. - Dosing Information - Omeprazole 10 milligrams (mg) orally once daily. - Dosing Information - Omeprazole alone (without hygienic-dietary or postural interventions) 20 milligrams (mg) twice daily for 12 weeks. - Dosing Information - Omeprazole 40 mg every 12 hours. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Symptomatic GERD - Omeprazole delayed-release capsules USP are indicated for the treatment of heartburn and other symptoms associated with GERD in pediatric patients. - Erosive Esophagitis - Omeprazole delayed-release capsules USP are indicated for the short-term treatment (4 to 8 weeks) of erosive esophagitis that has been diagnosed by endoscopy in pediatric patients. - The efficacy of omeprazole delayed-release capsules USP used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of erosive esophagitis or GERD symptoms (eg, heartburn), additional 4 to 8 week courses of omeprazole may be considered. - The recommended daily dose for pediatric patients 2 to 16 years of age is as follows: - Omeprazole delayed-release capsules USP are indicated to maintain healing of erosive esophagitis in pediatric patients. - Controlled studies do not extend beyond 12 months. - The recommended daily dose for pediatric patients 2 to 16 years of age is as follows: ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Omeprazole in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Low-dose omeprazole 1.1 to 1.25 milligrams/kilogram (mg/kg) daily. Omeprazole was titrated to a range of 1.9 to 2.5 mg/kg/day. # Contraindications - Omeprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria. # Warnings ### Precautions - Concomitant Gastric Malignancy - Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. - Atrophic Gastritis - Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole. - Clostridium difficile Associated Diarrhea - Published observational studies suggest that PPI therapy like omeprazole may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve. - Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. - Clostridium diffficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. - Interaction with Clopidogrel - Avoid concomitant use of omeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using omeprazole, consider alternative anti-platelet therapy. - Bone Fracture - Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines. - Hypomagnesemia - Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. - For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. - Concomitant Use of Omeprazole with St John’s Wort or Rifampin - Drugs which induce CYP2C19 or CYP3A4 (such as St John’s Wort or rifampin) can substantially decrease omeprazole concentrations. - Interactions with Diagnostic Investigations for Neuroendocrine Tumors - Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. - Concomitant Use of Omeprazole with Methotrexate - Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety data described below reflects exposure to omeprazole delayed-release capsules in 3096 patients from worldwide clinical trials (465 patients from US studies and 2,631 patients from international studies). Indications clinically studied in US trials included duodenal ulcer, resistant ulcer, and Zollinger-Ellison syndrome. The international clinical trials were double blind and open-label in design. The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) from omeprazole-treated patients enrolled in these studies included headache (6.9%), abdominal pain (5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and flatulence (2.7%). - Additional adverse reactions that were reported with an incidence ≥1% included acid regurgitation (1.9%), upper respiratory infection (1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia (1.3%), back pain (1.1%), and cough (1.1%). - The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less. - The clinical trial safety profile in pediatric patients who received omeprazole delayed-release capsules was similar to that in adult patients. Unique to the pediatric population, however, adverse reactions of the respiratory system were most frequently reported in the 2 to 16 year age group (18.5%). Similarly, accidental injuries were reported frequently in the 2 to 16 year age group (3.8%). - In clinical trials using either dual therapy with omeprazole and clarithromycin, or triple therapy with omeprazole, clarithromycin, and amoxicillin, no adverse reactions unique to these drug combinations were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, or amoxicillin alone. - Adverse reactions observed in controlled clinical trials using combination therapy with omeprazole and clarithromycin (n = 346) that differed from those previously described for omeprazole alone were taste perversion (15%), tongue discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu-syndrome (1%). - The most frequent adverse reactions observed in clinical trials using combination therapy with omeprazole, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of omeprazole delayed-release capsules. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria. Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema. Gynecomastia Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests . Clostridium difficile associated diarrhea Hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo Epistaxis, pharyngeal pain Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis Tinnitus, taste perversion Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis # Drug Interactions - Interference with Antiretroviral Therapy - Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction. - Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19. - Reduced concentrations of atazanavir and nelfinavir - For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. - Increased concentrations of saquinavir - For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in Cmax by 75%, and in Cmin by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with omeprazole. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. - There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole. - Drugs for Which Gastric pH Can Affect Bioavailability - Because of its profound and long lasting inhibition of gastric acid secretion, it is theoretically possible that omeprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, ampicillin esters, iron salts and erlotinib can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Therefore, patients may need to be monitored when digoxin is taken concomitantly with omeprazole. In the clinical trials, antacids were used concomitantly with the administration of omeprazole. - Effects on Hepatic Metabolism/Cytochrome P-450 Pathways - Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time. - Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with omeprazole. - Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered. When voriconazole (400 mg Q12h x 1 day, then 200 mg x 6 days) was given with omeprazole (40 mg once daily x 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole. - Omeprazole acts as an inhibitor of CYP 2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in crossover study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered. - Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased omeprazole serum levels. In a cross-over study in 12 healthy male subjects, St John’s wort (300 mg three times daily for 14 days), an inducer of CYP3A4, decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with omeprazole. - Clopidogrel - Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of omeprazole with clopidogrel. When using omeprazole, consider use of alternative anti-platelet therapy. - There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. - Tacrolimus - Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus. - Interactions with Investigations of Neuroendocrine Tumors - Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors.. - Combination Therapy with Clarithromycin - Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions. - Methotrexate - Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Risk Summary - There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. - Animal reproduction studies with omeprazole in rats and rabbits resulted in dose-dependent embryolethality at doses that were approximately 2.8 to 28 times the daily human dose of 40 mg - Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 57 times and 35 times, respectively, an oral human dose of 40 mg. However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 33.6 times an oral human dose of 40 mg. Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, omeprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Human Data - Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. - A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. - A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. - A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. - A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to nonteratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. - Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. - Animal Data - Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 28 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 28 times an oral human dose of 40 mg on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 2.8 to 28 times an oral human dose of 40 mg on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 2.8 to 28 times an oral human doses of 40 mg on a body surface area basis). - Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 57 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium. - A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 57 times an oral human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 33 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 16.8 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). - Effects on maternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg /kg/day (about 3.4 to 57 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). - A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Omeprazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Omeprazole during labor and delivery. ### Nursing Mothers - Omeprazole is present in human milk. Omeprazole concentrations were measured in breast milk of a woman following oral administration of 20 mg. The peak concentration of omeprazole in breast milk was less than 7% of the peak serum concentration. This concentration would correspond to 0.004 mg of omeprazole in 200 mL of milk. Caution should be exercised when omeprazole is administered to a nursing woman. ### Pediatric Use - Use of omeprazole in pediatric and adolescent patients 2 to 16 years of age for the treatment of GERD and maintenance of healing of erosive esophagitis is supported by a) extrapolation of results from adequate and well-controlled studies that supported the approval of omeprazole for adults, and b) safety and pharmacokinetic studies performed in pediatric and adolescent patients. The safety and effectiveness of omeprazole for the treatment of GERD in patients < 1 year of age have not been established. The safety and effectiveness of omeprazole for other pediatric uses have not been established. ### Geriatic Use - Omeprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. - Pharmacokinetic studies have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. However, no dosage adjustment is necessary in the elderly. ### Gender There is no FDA guidance on the use of Omeprazole with respect to specific gender populations. ### Race Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. ### Renal Impairment - No dosage reduction is necessary. ### Hepatic Impairment - Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Omeprazole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Omeprazole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Omeprazole in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Omeprazole in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience. Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. ### Management - No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive. - As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, contact a Poison Control Center at 1-800-222-1222. ## Chronic Overdose There is limited information regarding Chronic Overdose of Omeprazole in the drug label. # Pharmacology ## Mechanism of Action - Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more. ## Structure - The active ingredient in omeprazole delayed-release capsules USP is a substituted benzimidazole, 5-methoxy-¬2- sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C17H19N3O3S, with a molecular weight of 345.42. The structural formula is: - Omeprazole USP is a white to off-white crystalline powder that melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions. - Omeprazole USP is supplied as delayed-release capsules for oral administration. Each delayed-release capsule contains either 10 mg, 20 mg or 40 mg of omeprazole USP in the form of enteric-coated granules with the following inactive ingredients: anhydrous lactose, cetyl alcohol, di-sodium hydrogen phosphate dihydrate, hypromellose, hypromellose phthalate, mannitol, simethicone emulsion 30%, sodium lauryl sulfate and sugar sphere. - The capsule shell for omeprazole delayed-release capsules USP, 10 mg contains FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No.10, gelatin, FD&C Blue No.1, FD&C Red No. 3, sodium lauryl sulfate and titanium dioxide. - The capsule shell for omeprazole delayed-release capsules USP, 20 mg contains FD&C Blue No.1, FD&C Red No.3, gelatin, sodium lauryl sulfate and titanium dioxide. - The capsule shell for omeprazole delayed-release capsules USP, 40 mg contains FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No.10, gelatin, FD&C Blue No.1, FD&C Red No. 3, sodium lauryl sulfate and titanium dioxide. - The imprinting ink has the following components: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide and potassium hydroxide. ## Pharmacodynamics - Antisecretory Activity - After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days. - Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of omeprazole in normal volunteers and patients are shown below. The “max” value represents determinations at a time of maximum effect (2 to 6 hours after dosing), while “min” values are those 24 hours after the last dose of omeprazole. - Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24-hour intragastric acidity in some patients. - Serum Gastrin Effects - In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H2 receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy. - Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. - Enterochromaffin-like (ECL) Cell Effects - Human gastric biopsy specimens have been obtained from more than 3000 patients (both children and adults) treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions. - Other Effects - Systemic effects of omeprazole in the CNS, cardiovascular and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. - No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. - However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased. - As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment. - The course of Barrett’s esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of omeprazole 40 mg twice daily for 12 months followed by 20 mg twice daily for 12 months or ranitidine 300 mg twice daily for 24 months. No clinically significant impact on Barrett’s mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett’s mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett’s mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter. ## Pharmacokinetics - Absorption - Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30 to 40% at doses of 20 to 40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500 to 600 mL/min. - Based on a relative bioavailability study, the AUC and Cmax of omeprazole delayed-release capsules were 88%. - The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole delayed-release capsules. - Omeprazole delayed-release capsule 40 mg was bioequivalent when administered with and without applesauce. However, omeprazole delayed-release capsule 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for omeprazole delayed-release capsule 20 mg. The clinical relevance of this finding is unknown. - Distribution - Protein binding is approximately 95%. - Metabolism - Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. - Excretion - Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity. - Combination Therapy with Antimicrobials - Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of omeprazole were increased (Cmax, AUC 0-24, and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in omeprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin. - The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole. - Concomitant Use with Clopidogrel - In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. - Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when coadministered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period. - In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction. - Special Populations - Geriatric Population - The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. - Pediatric Use - The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age: - Hepatic Impairment - In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared with an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in normals of 0.5 to 1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in normal subjects. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired should be considered. - Renal Impairment - In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m2, the disposition of omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. No dose reduction is necessary in patients with renal impairment. - Asian Population - In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared with Caucasians. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for Asian subjects should be considered. - Omeprazole and clarithromycin dual therapy and omeprazole, clarithromycin and amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections. - Helicobacter - Helicobacter pylori-Pretreatment Resistance - Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3% (41/439) in omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). - Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 µg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin and amoxicillin study arm. One patient had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 µg/mL by Etest®. - Patients not eradicated of H. pylori following omeprazole/clarithromycin/amoxicillin triple therapy or omeprazole/clarithromycin dual therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy, omeprazole/clarithromycin/amoxicillin triple therapy, or other regimens which include clarithromycin as the sole antimicrobial agent. - Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes - In the triple therapy clinical trials, 84.9% (157/185) of the patients in the omeprazole/clarithromycin/amoxicillin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. - Effects on Gastrointestinal Microbial Ecology - Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile. ## Nonclinical Toxicology - In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.35 to 28 times a human dose of 40 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 2.8 times a human dose of 40 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.2 times the human dose of 40 mg/day, based on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 28 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive. - Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay. - Omeprazole at oral doses up to 138 mg/kg/day in rats (about 28 times an oral human dose of 40 mg on a body surface area basis) was found to have no effect on fertility and reproductive performance. - In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists. - Reproduction Studies - Reproductive Toxicology Studies - Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 28 times the human dose of 40 mg/day on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 28 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 2.8 to 28 times the human dose of 40 mg/day on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 2.8 to 28 times the human dose of 40 mg/day on a body surface area basis). - Juvenile Animal Study - A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg /kg/day (about 17 to 57 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg /kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole. # Clinical Studies - Active Duodenal Ulcer - In a multicenter, double-blind, placebo-controlled study of 147 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 2 and 4 weeks was significantly higher with omeprazole 20 mg once daily than with placebo (p ≤ 0.01). - Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with omeprazole 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received omeprazole had complete relief of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01). - In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with omeprazole 20 mg once daily than with ranitidine 150 mg b.i.d. (p < 0.01). - Healing occurred significantly faster in patients treated with omeprazole than in those treated with ranitidine 150 mg b.i.d. (p < 0.01). - In a foreign multinational randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 20 mg and 40 mg of omeprazole were compared with 150 mg b.i.d. of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of omeprazole were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of omeprazole, and at 8 weeks there was no significant difference between any of the active drugs. - H. pylori Eradication in Patients with Duodenal Ulcer Disease - Triple Therapy(omeprazole/clarithromycin/amoxicillin - Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared omeprazole plus clarithromycin plus amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were conducted in patients with an active duodenal ulcer, and the other study (3) was conducted in patients with a history of a duodenal ulcer in the past 5 years but without an ulcer present at the time of enrollment. The dose regimen in the studies was omeprazole 20 mg twice daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days. In studies 1 and 2, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg once daily. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 1 and 2 only). H. pylori status was determined by CLOtest®, histology and culture in all three studies. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive. - The combination of omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H. pylori. - Dual Therapy (omeprazole/clarithromycin) - Four randomized, double-blind, multi-center studies (4, 5, 6, and 7) evaluated omeprazole 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days, followed by omeprazole 20 mg once daily, (Studies 4, 5, and 7) or by omeprazole 40 mg once daily (Study 6) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies 4 and 5 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study 4 and 228 patients in Study 5. These studies compared the combination regimen to omeprazole and clarithromycin monotherapies. Studies 6 and 7 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in Study 6 and 208 patients in Study 7. These studies compared the combination regimen with omeprazole monotherapy. The results for the efficacy analyses for these studies are described below. H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated of H. pylori. In the per-protocol analysis, the following patients were excluded: dropouts, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication because they were found to have an ulcer at the end of treatment. - The combination of omeprazole and clarithromycin was effective in eradicating H. pylori. - Ulcer healing was not significantly different when clarithromycin was added to omeprazole therapy compared with omeprazole therapy alone. - The combination of omeprazole and clarithromycin was effective in eradicating H. pylori and reduced duodenal ulcer recurrence. - In a U.S. multicenter, double-blind, study of omeprazole 40 mg once daily, 20 mg once daily, and placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were obtained. - For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg was significantly more effective than 20 mg at 8 weeks. - In a foreign, multinational, double-blind study of 602 patients with endoscopically diagnosed gastric ulcer, omeprazole 40 mg once daily, 20 mg once daily, and ranitidine 150 mg twice a day were evaluated. - Symptomatic GERD - A placebo-controlled study was conducted in Scandinavia to compare the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD patients without erosive esophagitis. Results are shown below. - In a U.S. multicenter double-blind placebo controlled study of 20 mg or 40 mg of omeprazole delayed-release capsules in patients with symptoms of GERD and endoscopically diagnosed erosive esophagitis of grade 2 or above, the percentage healing rates (per protocol) were as follows: - In this study, the 40 mg dose was not superior to the 20 mg dose of omeprazole in the percentage healing rate. Other controlled clinical trials have also shown that omeprazole is effective in severe GERD. In comparisons with histamine H2 receptor antagonists in patients with erosive esophagitis, grade 2 or above, omeprazole in a dose of 20 mg was significantly more effective than the active controls. Complete daytime and nighttime heartburn relief occurred significantly faster (p < 0.01) in patients treated with omeprazole than in those taking placebo or histamine H2- receptor antagonists. - In this and five other controlled GERD studies, significantly more patients taking 20 mg omeprazole (84%) reported complete relief of GERD symptoms than patients receiving placebo (12%). - Long Term Maintenance of Healing of Erosive Esophagitis - In a U.S. double-blind, randomized, multicenter, placebo controlled study, two dose regimens of omeprazole were studied in patients with endoscopically confirmed healed esophagitis. Results to determine maintenance of healing of erosive esophagitis are shown below. - In an international multicenter double-blind study, omeprazole 20 mg daily and 10 mg daily were compared with ranitidine 150 mg twice daily in patients with endoscopically confirmed healed esophagitis. The table below provides the results of this study for maintenance of healing of erosive esophagitis. - In patients who initially had grades 3 or 4 erosive esophagitis, for maintenance after healing 20 mg daily of omeprazole was effective, while 10 mg did not demonstrate effectiveness. - In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple endocrine adenomas, omeprazole delayed-release capsules significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg every other day to 360 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery, and below 5 mEq/hr in patients with prior gastric surgery. - Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients omeprazole was well tolerated at these high dose levels for prolonged periods (> 5 years in some patients). In most ZE patients, serum gastrin levels were not modified by omeprazole. However, in some patients serum gastrin increased to levels greater than those present prior to initiation of omeprazole therapy. At least 11 patients with ZE syndrome on long-term treatment with omeprazole developed gastric carcinoids. These findings are believed to be a manifestation of the underlying condition, which is known to be associated with such tumors, rather than the result of the administration of omeprazole. - Symptomatic GERD - The effectiveness of omeprazole for the treatment of nonerosive GERD in pediatric patients 2 to 16 years of age is based in part on data obtained from pediatric patients in an uncontrolled Phase III study. - The study enrolled 113 pediatric patients 2 to 16 years of age with a history of symptoms suggestive of nonerosive GERD. Patients were administered a single dose of omeprazole (10 mg or 20 mg, based on body weight) for 4 weeks either as an intact capsule or as an open capsule in applesauce. Successful response was defined as no moderate or severe episodes of either pain-related symptoms or vomiting/regurgitation during the last 4 days of treatment. Results showed success rates of 60% (9/15; 10 mg omeprazole) and 59% (58/98; 20 mg omeprazole), respectively. - Healing of Erosive Esophagitis - In an uncontrolled, open-label dose-titration study, healing of erosive esophagitis in pediatric patients 1 to 16 years of age required doses that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7 mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than 6% of a 24-hour study). After titration, patients remained on treatment for 3 months. Forty-four percent of the patients were healed on a dose of 0.7 mg/kg body weight; most of the remaining patients were healed with 1.4 mg/kg after an additional 3 months’ treatment. Erosive esophagitis was healed in 51 of 57 (90%) children who completed the first course of treatment in the healing phase of the study. In addition, after 3 months of treatment, 33% of the children had no overall symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation/vomiting. - Maintenance of Healing of Erosive Esophagitis - In an uncontrolled, open-label study of maintenance of healing of erosive esophagitis in 46 pediatric patients, 54% of patients required half the healing dose. The remaining patients increased the healing dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire maintenance period, or returned to half the dose before completion. Of the 46 patients who entered the maintenance phase, 19 (41%) had no relapse. In addition, maintenance therapy in erosive esophagitis patients resulted in 63% of patients having no overall symptoms. # How Supplied - Omeprazole delayed-release capsules USP, 10 mg, are size ‘3’ two piece hard gelatin capsule with purple blue body with “G” imprinting in black ink and orange cap with “G230” imprinting in black ink. The capsules are filled with white to off-white pellets. They are supplied as follows: - NDC 68462-230-30 bottles of 30 - NDC 68462-230-01 bottles of 100 - NDC 68462-230-10 bottles of 1000 - Omeprazole delayed-release capsules USP, 20 mg, are size ‘2’ two piece hard gelatin capsule with purple blue body with “G” imprinting in black ink and purple blue cap with “G231” imprinting in black ink. The capsules are filled with white to off-white pellets. They are supplied as follows: - NDC 68462-231-30 bottles of 30 - NDC 68462-231-01 bottles of 100 - NDC 68462-231-10 bottles of 1000 - Omeprazole delayed-release capsules USP, 40 mg, are size ‘1’ two piece hard gelatin capsule with orange body with ‘G’ imprinting in black ink and purple blue cap with ‘G232’ imprinting in black ink. The capsules are filled with white to off-white pellets. They are supplied as follows: - NDC 68462-232-30 bottles of 30 - NDC 68462-232-01 bottles of 100 - Storage - Store omeprazole delayed-release capsules in a tight container protected from light and moisture. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). ## Storage There is limited information regarding Omeprazole Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Omeprazole should be taken before eating. Patients should be informed that the omeprazole delayed-release capsule should be swallowed whole. - For patients who have difficulty swallowing capsules, the contents of an omeprazole delayed-release capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or crushed. The pellets/applesauce mixture should not be stored for future use. - Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea. - Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia. # Precautions with Alcohol - Alcohol-Omeprazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - OMEPRAZOLE® # Look-Alike Drug Names - proton pump inhibitors® — aripiprazole® - omeprazole® — fomepizole® - Losec® — Lasix® - Losec® — PROzac® - Prilosec® — Pristiq® - PriLOSEC® — PROzac® # Drug Shortage Status # Price	Omeprazole Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Omeprazole is a proton pump inhibitor that is FDA approved for the {{{indicationType}}} of duodenal ulcer, gastric ulcer, gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis and pathological hypersecretory conditions. Common adverse reactions include headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Short-Term Treatment of Active Duodenal Ulcer - The recommended adult oral dose of omeprazole delayed-release capsule USP is 20 mg once daily. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. - H. pylori Eradication for the Reduction of the Risk of Duodenal Ulcer Recurrence - Triple Therapy (omeprazole/clarithromycin/amoxicillin) The recommended adult oral regimen is omeprazole delayed-release capsule USP 20 mg plus clarithromycin 500 mg plus amoxicillin 1000 mg each given twice daily for 10 days. In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole delayed-release capsule USP 20 mg once daily is recommended for ulcer healing and symptom relief. - The recommended adult oral regimen is omeprazole delayed-release capsule USP 20 mg plus clarithromycin 500 mg plus amoxicillin 1000 mg each given twice daily for 10 days. In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole delayed-release capsule USP 20 mg once daily is recommended for ulcer healing and symptom relief. - Dual Therapy (omeprazole/clarithromycin) The recommended adult oral regimen is omeprazole delayed-release capsule USP 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days. In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of omeprazole delayed-release capsule USP 20 mg once daily is recommended for ulcer healing and symptom relief. - The recommended adult oral regimen is omeprazole delayed-release capsule USP 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days. In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of omeprazole delayed-release capsule USP 20 mg once daily is recommended for ulcer healing and symptom relief. - Omeprazole delayed-release capsules USP are indicated for short-term treatment (4 to 8 weeks) of active benign gastric ulcer in adults. - The recommended adult oral dose is 40 mg once daily for 4 to 8 weeks. - Symptomatic GERD - Omeprazole delayed-release capsules USP are indicated for the treatment of heartburn and other symptoms associated with GERD in adults. - The recommended adult oral dose for the treatment of patients with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4 weeks. - Erosive Esophagitis - Omeprazole delayed-release capsules USP are indicated for the short-term treatment (4 to 8 weeks) of erosive esophagitis that has been diagnosed by endoscopy in adults. - The efficacy of omeprazole delayed-release capsules USP used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of erosive esophagitis or GERD symptoms (eg, heartburn), additional 4 to 8 week courses of omeprazole may be considered. - The recommended adult oral dose for the treatment of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4 to 8 weeks. - Omeprazole delayed-release capsules USP are indicated to maintain healing of erosive esophagitis in adults. - Controlled studies do not extend beyond 12 months. - The recommended adult oral dose is 20 mg daily. - Omeprazole delayed-release capsules USP are indicated for the long-term treatment of pathological hypersecretory conditions (eg, Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) in adults. - The dosage of omeprazole delayed-release capsule USP in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 120 mg three times daily have been administered. Daily dosages of greater than 80 mg should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have been treated continuously with omeprazole delayed-release capsule USP for more than 5 years. ## Off-Label Use and Dosage (Adult) ### Non–Guideline-Supported Use - Dosing Information - Omeprazole dosing was 40 milligrams. - Dosing Information - Omeprazole 20 mg once a day. - Dosing Information - Omeprazole (20 milligrams (mg) daily) remained in remission throughout the 6-month. - Dosing Information - Omeprazole 20 milligrams once daily for 6 months. - Dosing Information - Omeprazole 20 to 40 mg/day. - Dosing Information - 2-week course of omeprazole 40 milligrams daily combined with either amoxicillin (minimum dose of 2 grams daily) or clarithromycin (1 gram daily). - Dosing Information - Omeprazole (40 milligrams (mg) in the morning and 20 mg in the evening) for 7 days. - Dosing Information - Omeprazole 80 milligrams (mg) intravenous (IV) bolus, followed by 8 mg per hour IV continuous infusion. - Dosing Information - Omeprazole 40 milligrams (mg). - Dosing Information - Omeprazole 20 milligrams twice daily. - Dosing Information - Omeprazole 10 milligrams (mg) orally once daily. - Dosing Information - Omeprazole alone (without hygienic-dietary or postural interventions) 20 milligrams (mg) twice daily for 12 weeks. - Dosing Information - Omeprazole 40 mg every 12 hours. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Symptomatic GERD - Omeprazole delayed-release capsules USP are indicated for the treatment of heartburn and other symptoms associated with GERD in pediatric patients. - Erosive Esophagitis - Omeprazole delayed-release capsules USP are indicated for the short-term treatment (4 to 8 weeks) of erosive esophagitis that has been diagnosed by endoscopy in pediatric patients. - The efficacy of omeprazole delayed-release capsules USP used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of erosive esophagitis or GERD symptoms (eg, heartburn), additional 4 to 8 week courses of omeprazole may be considered. - The recommended daily dose for pediatric patients 2 to 16 years of age is as follows: - Omeprazole delayed-release capsules USP are indicated to maintain healing of erosive esophagitis in pediatric patients. - Controlled studies do not extend beyond 12 months. - The recommended daily dose for pediatric patients 2 to 16 years of age is as follows: ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Omeprazole in pediatric patients. ### Non–Guideline-Supported Use - Dosing Information - Low-dose omeprazole 1.1 to 1.25 milligrams/kilogram (mg/kg) daily. Omeprazole was titrated to a range of 1.9 to 2.5 mg/kg/day. # Contraindications - Omeprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria. # Warnings ### Precautions - Concomitant Gastric Malignancy - Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. - Atrophic Gastritis - Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole. - Clostridium difficile Associated Diarrhea - Published observational studies suggest that PPI therapy like omeprazole may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve. - Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. - Clostridium diffficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. - Interaction with Clopidogrel - Avoid concomitant use of omeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using omeprazole, consider alternative anti-platelet therapy. - Bone Fracture - Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines. - Hypomagnesemia - Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. - For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. - Concomitant Use of Omeprazole with St John’s Wort or Rifampin - Drugs which induce CYP2C19 or CYP3A4 (such as St John’s Wort or rifampin) can substantially decrease omeprazole concentrations. - Interactions with Diagnostic Investigations for Neuroendocrine Tumors - Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. - Concomitant Use of Omeprazole with Methotrexate - Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - The safety data described below reflects exposure to omeprazole delayed-release capsules in 3096 patients from worldwide clinical trials (465 patients from US studies and 2,631 patients from international studies). Indications clinically studied in US trials included duodenal ulcer, resistant ulcer, and Zollinger-Ellison syndrome. The international clinical trials were double blind and open-label in design. The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) from omeprazole-treated patients enrolled in these studies included headache (6.9%), abdominal pain (5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and flatulence (2.7%). - Additional adverse reactions that were reported with an incidence ≥1% included acid regurgitation (1.9%), upper respiratory infection (1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia (1.3%), back pain (1.1%), and cough (1.1%). - The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less. - The clinical trial safety profile in pediatric patients who received omeprazole delayed-release capsules was similar to that in adult patients. Unique to the pediatric population, however, adverse reactions of the respiratory system were most frequently reported in the 2 to 16 year age group (18.5%). Similarly, accidental injuries were reported frequently in the 2 to 16 year age group (3.8%). - In clinical trials using either dual therapy with omeprazole and clarithromycin, or triple therapy with omeprazole, clarithromycin, and amoxicillin, no adverse reactions unique to these drug combinations were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, or amoxicillin alone. - Adverse reactions observed in controlled clinical trials using combination therapy with omeprazole and clarithromycin (n = 346) that differed from those previously described for omeprazole alone were taste perversion (15%), tongue discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu-syndrome (1%). - The most frequent adverse reactions observed in clinical trials using combination therapy with omeprazole, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of omeprazole delayed-release capsules. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria. Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema. Gynecomastia Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]. Clostridium difficile associated diarrhea Hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo Epistaxis, pharyngeal pain Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis Tinnitus, taste perversion Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis # Drug Interactions - Interference with Antiretroviral Therapy - Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction. - Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19. - Reduced concentrations of atazanavir and nelfinavir - For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. - Increased concentrations of saquinavir - For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in Cmax by 75%, and in Cmin by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with omeprazole. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. - There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole. - Drugs for Which Gastric pH Can Affect Bioavailability - Because of its profound and long lasting inhibition of gastric acid secretion, it is theoretically possible that omeprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, ampicillin esters, iron salts and erlotinib can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Therefore, patients may need to be monitored when digoxin is taken concomitantly with omeprazole. In the clinical trials, antacids were used concomitantly with the administration of omeprazole. - Effects on Hepatic Metabolism/Cytochrome P-450 Pathways - Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time. - Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with omeprazole. - Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered. When voriconazole (400 mg Q12h x 1 day, then 200 mg x 6 days) was given with omeprazole (40 mg once daily x 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole. - Omeprazole acts as an inhibitor of CYP 2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in crossover study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered. - Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased omeprazole serum levels. In a cross-over study in 12 healthy male subjects, St John’s wort (300 mg three times daily for 14 days), an inducer of CYP3A4, decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with omeprazole. - Clopidogrel - Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of omeprazole with clopidogrel. When using omeprazole, consider use of alternative anti-platelet therapy. - There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. - Tacrolimus - Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus. - Interactions with Investigations of Neuroendocrine Tumors - Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors.. - Combination Therapy with Clarithromycin - Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions. - Methotrexate - Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Risk Summary - There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. - Animal reproduction studies with omeprazole in rats and rabbits resulted in dose-dependent embryolethality at doses that were approximately 2.8 to 28 times the daily human dose of 40 mg - Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 57 times and 35 times, respectively, an oral human dose of 40 mg. However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 33.6 times an oral human dose of 40 mg. Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, omeprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Human Data - Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. - A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. - A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. - A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. - A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to nonteratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. - Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. - Animal Data - Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 28 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 28 times an oral human dose of 40 mg on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 2.8 to 28 times an oral human dose of 40 mg on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 2.8 to 28 times an oral human doses of 40 mg on a body surface area basis). - Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 57 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium. - A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 57 times an oral human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 33 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 16.8 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). - Effects on maternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg /kg/day (about 3.4 to 57 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). - A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Omeprazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Omeprazole during labor and delivery. ### Nursing Mothers - Omeprazole is present in human milk. Omeprazole concentrations were measured in breast milk of a woman following oral administration of 20 mg. The peak concentration of omeprazole in breast milk was less than 7% of the peak serum concentration. This concentration would correspond to 0.004 mg of omeprazole in 200 mL of milk. Caution should be exercised when omeprazole is administered to a nursing woman. ### Pediatric Use - Use of omeprazole in pediatric and adolescent patients 2 to 16 years of age for the treatment of GERD and maintenance of healing of erosive esophagitis is supported by a) extrapolation of results from adequate and well-controlled studies that supported the approval of omeprazole for adults, and b) safety and pharmacokinetic studies performed in pediatric and adolescent patients. The safety and effectiveness of omeprazole for the treatment of GERD in patients < 1 year of age have not been established. The safety and effectiveness of omeprazole for other pediatric uses have not been established. ### Geriatic Use - Omeprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. - Pharmacokinetic studies have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. However, no dosage adjustment is necessary in the elderly. ### Gender There is no FDA guidance on the use of Omeprazole with respect to specific gender populations. ### Race Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. ### Renal Impairment - No dosage reduction is necessary. ### Hepatic Impairment - Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Omeprazole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Omeprazole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Omeprazole in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Omeprazole in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience. Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. ### Management - No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive. - As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, contact a Poison Control Center at 1-800-222-1222. ## Chronic Overdose There is limited information regarding Chronic Overdose of Omeprazole in the drug label. # Pharmacology ## Mechanism of Action - Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more. ## Structure - The active ingredient in omeprazole delayed-release capsules USP is a substituted benzimidazole, 5-methoxy-¬2-[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C17H19N3O3S, with a molecular weight of 345.42. The structural formula is: - Omeprazole USP is a white to off-white crystalline powder that melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions. - Omeprazole USP is supplied as delayed-release capsules for oral administration. Each delayed-release capsule contains either 10 mg, 20 mg or 40 mg of omeprazole USP in the form of enteric-coated granules with the following inactive ingredients: anhydrous lactose, cetyl alcohol, di-sodium hydrogen phosphate dihydrate, hypromellose, hypromellose phthalate, mannitol, simethicone emulsion 30%, sodium lauryl sulfate and sugar sphere. - The capsule shell for omeprazole delayed-release capsules USP, 10 mg contains FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No.10, gelatin, FD&C Blue No.1, FD&C Red No. 3, sodium lauryl sulfate and titanium dioxide. - The capsule shell for omeprazole delayed-release capsules USP, 20 mg contains FD&C Blue No.1, FD&C Red No.3, gelatin, sodium lauryl sulfate and titanium dioxide. - The capsule shell for omeprazole delayed-release capsules USP, 40 mg contains FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No.10, gelatin, FD&C Blue No.1, FD&C Red No. 3, sodium lauryl sulfate and titanium dioxide. - The imprinting ink has the following components: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide and potassium hydroxide. ## Pharmacodynamics - Antisecretory Activity - After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days. - Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of omeprazole in normal volunteers and patients are shown below. The “max” value represents determinations at a time of maximum effect (2 to 6 hours after dosing), while “min” values are those 24 hours after the last dose of omeprazole. - Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24-hour intragastric acidity in some patients. - Serum Gastrin Effects - In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H2 receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy. - Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. - Enterochromaffin-like (ECL) Cell Effects - Human gastric biopsy specimens have been obtained from more than 3000 patients (both children and adults) treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions. - Other Effects - Systemic effects of omeprazole in the CNS, cardiovascular and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. - No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. - However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased. - As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment. - The course of Barrett’s esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of omeprazole 40 mg twice daily for 12 months followed by 20 mg twice daily for 12 months or ranitidine 300 mg twice daily for 24 months. No clinically significant impact on Barrett’s mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett’s mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett’s mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter. ## Pharmacokinetics - Absorption - Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30 to 40% at doses of 20 to 40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500 to 600 mL/min. - Based on a relative bioavailability study, the AUC and Cmax of omeprazole delayed-release capsules were 88%. - The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole delayed-release capsules. - Omeprazole delayed-release capsule 40 mg was bioequivalent when administered with and without applesauce. However, omeprazole delayed-release capsule 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for omeprazole delayed-release capsule 20 mg. The clinical relevance of this finding is unknown. - Distribution - Protein binding is approximately 95%. - Metabolism - Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. - Excretion - Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity. - Combination Therapy with Antimicrobials - Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of omeprazole were increased (Cmax, AUC 0-24, and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in omeprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin. - The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole. - Concomitant Use with Clopidogrel - In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. - Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when coadministered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period. - In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction. - Special Populations - Geriatric Population - The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. - Pediatric Use - The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age: - Hepatic Impairment - In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared with an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in normals of 0.5 to 1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in normal subjects. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired should be considered. - Renal Impairment - In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m2, the disposition of omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. No dose reduction is necessary in patients with renal impairment. - Asian Population - In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared with Caucasians. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for Asian subjects should be considered. - Omeprazole and clarithromycin dual therapy and omeprazole, clarithromycin and amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections. - Helicobacter - Helicobacter pylori-Pretreatment Resistance - Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3% (41/439) in omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). - Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 µg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin and amoxicillin study arm. One patient had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 µg/mL by Etest®. - Patients not eradicated of H. pylori following omeprazole/clarithromycin/amoxicillin triple therapy or omeprazole/clarithromycin dual therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy, omeprazole/clarithromycin/amoxicillin triple therapy, or other regimens which include clarithromycin as the sole antimicrobial agent. - Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes - In the triple therapy clinical trials, 84.9% (157/185) of the patients in the omeprazole/clarithromycin/amoxicillin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. - Effects on Gastrointestinal Microbial Ecology - Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly also Clostridium difficile. ## Nonclinical Toxicology - In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.35 to 28 times a human dose of 40 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 2.8 times a human dose of 40 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.2 times the human dose of 40 mg/day, based on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 28 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive. - Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay. - Omeprazole at oral doses up to 138 mg/kg/day in rats (about 28 times an oral human dose of 40 mg on a body surface area basis) was found to have no effect on fertility and reproductive performance. - In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists. - Reproduction Studies - Reproductive Toxicology Studies - Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 28 times the human dose of 40 mg/day on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 28 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 2.8 to 28 times the human dose of 40 mg/day on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 2.8 to 28 times the human dose of 40 mg/day on a body surface area basis). - Juvenile Animal Study - A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg /kg/day (about 17 to 57 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg /kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole. # Clinical Studies - Active Duodenal Ulcer - In a multicenter, double-blind, placebo-controlled study of 147 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 2 and 4 weeks was significantly higher with omeprazole 20 mg once daily than with placebo (p ≤ 0.01). - Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with omeprazole 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received omeprazole had complete relief of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01). - In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with omeprazole 20 mg once daily than with ranitidine 150 mg b.i.d. (p < 0.01). - Healing occurred significantly faster in patients treated with omeprazole than in those treated with ranitidine 150 mg b.i.d. (p < 0.01). - In a foreign multinational randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 20 mg and 40 mg of omeprazole were compared with 150 mg b.i.d. of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of omeprazole were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of omeprazole, and at 8 weeks there was no significant difference between any of the active drugs. - H. pylori Eradication in Patients with Duodenal Ulcer Disease - Triple Therapy(omeprazole/clarithromycin/amoxicillin - Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared omeprazole plus clarithromycin plus amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were conducted in patients with an active duodenal ulcer, and the other study (3) was conducted in patients with a history of a duodenal ulcer in the past 5 years but without an ulcer present at the time of enrollment. The dose regimen in the studies was omeprazole 20 mg twice daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days. In studies 1 and 2, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg once daily. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 1 and 2 only). H. pylori status was determined by CLOtest®, histology and culture in all three studies. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive. - The combination of omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H. pylori. - Dual Therapy (omeprazole/clarithromycin) - Four randomized, double-blind, multi-center studies (4, 5, 6, and 7) evaluated omeprazole 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days, followed by omeprazole 20 mg once daily, (Studies 4, 5, and 7) or by omeprazole 40 mg once daily (Study 6) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies 4 and 5 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study 4 and 228 patients in Study 5. These studies compared the combination regimen to omeprazole and clarithromycin monotherapies. Studies 6 and 7 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in Study 6 and 208 patients in Study 7. These studies compared the combination regimen with omeprazole monotherapy. The results for the efficacy analyses for these studies are described below. H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated of H. pylori. In the per-protocol analysis, the following patients were excluded: dropouts, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication because they were found to have an ulcer at the end of treatment. - The combination of omeprazole and clarithromycin was effective in eradicating H. pylori. - Ulcer healing was not significantly different when clarithromycin was added to omeprazole therapy compared with omeprazole therapy alone. - The combination of omeprazole and clarithromycin was effective in eradicating H. pylori and reduced duodenal ulcer recurrence. - In a U.S. multicenter, double-blind, study of omeprazole 40 mg once daily, 20 mg once daily, and placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were obtained. - For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg was significantly more effective than 20 mg at 8 weeks. - In a foreign, multinational, double-blind study of 602 patients with endoscopically diagnosed gastric ulcer, omeprazole 40 mg once daily, 20 mg once daily, and ranitidine 150 mg twice a day were evaluated. - Symptomatic GERD - A placebo-controlled study was conducted in Scandinavia to compare the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD patients without erosive esophagitis. Results are shown below. - In a U.S. multicenter double-blind placebo controlled study of 20 mg or 40 mg of omeprazole delayed-release capsules in patients with symptoms of GERD and endoscopically diagnosed erosive esophagitis of grade 2 or above, the percentage healing rates (per protocol) were as follows: - In this study, the 40 mg dose was not superior to the 20 mg dose of omeprazole in the percentage healing rate. Other controlled clinical trials have also shown that omeprazole is effective in severe GERD. In comparisons with histamine H2 receptor antagonists in patients with erosive esophagitis, grade 2 or above, omeprazole in a dose of 20 mg was significantly more effective than the active controls. Complete daytime and nighttime heartburn relief occurred significantly faster (p < 0.01) in patients treated with omeprazole than in those taking placebo or histamine H2- receptor antagonists. - In this and five other controlled GERD studies, significantly more patients taking 20 mg omeprazole (84%) reported complete relief of GERD symptoms than patients receiving placebo (12%). - Long Term Maintenance of Healing of Erosive Esophagitis - In a U.S. double-blind, randomized, multicenter, placebo controlled study, two dose regimens of omeprazole were studied in patients with endoscopically confirmed healed esophagitis. Results to determine maintenance of healing of erosive esophagitis are shown below. - In an international multicenter double-blind study, omeprazole 20 mg daily and 10 mg daily were compared with ranitidine 150 mg twice daily in patients with endoscopically confirmed healed esophagitis. The table below provides the results of this study for maintenance of healing of erosive esophagitis. - In patients who initially had grades 3 or 4 erosive esophagitis, for maintenance after healing 20 mg daily of omeprazole was effective, while 10 mg did not demonstrate effectiveness. - In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple endocrine adenomas, omeprazole delayed-release capsules significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg every other day to 360 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery, and below 5 mEq/hr in patients with prior gastric surgery. - Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients omeprazole was well tolerated at these high dose levels for prolonged periods (> 5 years in some patients). In most ZE patients, serum gastrin levels were not modified by omeprazole. However, in some patients serum gastrin increased to levels greater than those present prior to initiation of omeprazole therapy. At least 11 patients with ZE syndrome on long-term treatment with omeprazole developed gastric carcinoids. These findings are believed to be a manifestation of the underlying condition, which is known to be associated with such tumors, rather than the result of the administration of omeprazole. - Symptomatic GERD - The effectiveness of omeprazole for the treatment of nonerosive GERD in pediatric patients 2 to 16 years of age is based in part on data obtained from pediatric patients in an uncontrolled Phase III study. - The study enrolled 113 pediatric patients 2 to 16 years of age with a history of symptoms suggestive of nonerosive GERD. Patients were administered a single dose of omeprazole (10 mg or 20 mg, based on body weight) for 4 weeks either as an intact capsule or as an open capsule in applesauce. Successful response was defined as no moderate or severe episodes of either pain-related symptoms or vomiting/regurgitation during the last 4 days of treatment. Results showed success rates of 60% (9/15; 10 mg omeprazole) and 59% (58/98; 20 mg omeprazole), respectively. - Healing of Erosive Esophagitis - In an uncontrolled, open-label dose-titration study, healing of erosive esophagitis in pediatric patients 1 to 16 years of age required doses that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7 mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than 6% of a 24-hour study). After titration, patients remained on treatment for 3 months. Forty-four percent of the patients were healed on a dose of 0.7 mg/kg body weight; most of the remaining patients were healed with 1.4 mg/kg after an additional 3 months’ treatment. Erosive esophagitis was healed in 51 of 57 (90%) children who completed the first course of treatment in the healing phase of the study. In addition, after 3 months of treatment, 33% of the children had no overall symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation/vomiting. - Maintenance of Healing of Erosive Esophagitis - In an uncontrolled, open-label study of maintenance of healing of erosive esophagitis in 46 pediatric patients, 54% of patients required half the healing dose. The remaining patients increased the healing dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire maintenance period, or returned to half the dose before completion. Of the 46 patients who entered the maintenance phase, 19 (41%) had no relapse. In addition, maintenance therapy in erosive esophagitis patients resulted in 63% of patients having no overall symptoms. # How Supplied - Omeprazole delayed-release capsules USP, 10 mg, are size ‘3’ two piece hard gelatin capsule with purple blue body with “G” imprinting in black ink and orange cap with “G230” imprinting in black ink. The capsules are filled with white to off-white pellets. They are supplied as follows: - NDC 68462-230-30 bottles of 30 - NDC 68462-230-01 bottles of 100 - NDC 68462-230-10 bottles of 1000 - Omeprazole delayed-release capsules USP, 20 mg, are size ‘2’ two piece hard gelatin capsule with purple blue body with “G” imprinting in black ink and purple blue cap with “G231” imprinting in black ink. The capsules are filled with white to off-white pellets. They are supplied as follows: - NDC 68462-231-30 bottles of 30 - NDC 68462-231-01 bottles of 100 - NDC 68462-231-10 bottles of 1000 - Omeprazole delayed-release capsules USP, 40 mg, are size ‘1’ two piece hard gelatin capsule with orange body with ‘G’ imprinting in black ink and purple blue cap with ‘G232’ imprinting in black ink. The capsules are filled with white to off-white pellets. They are supplied as follows: - NDC 68462-232-30 bottles of 30 - NDC 68462-232-01 bottles of 100 - Storage - Store omeprazole delayed-release capsules in a tight container protected from light and moisture. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). ## Storage There is limited information regarding Omeprazole Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Omeprazole should be taken before eating. Patients should be informed that the omeprazole delayed-release capsule should be swallowed whole. - For patients who have difficulty swallowing capsules, the contents of an omeprazole delayed-release capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or crushed. The pellets/applesauce mixture should not be stored for future use. - Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea. - Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia. # Precautions with Alcohol - Alcohol-Omeprazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - OMEPRAZOLE®[3] # Look-Alike Drug Names - proton pump inhibitors® — aripiprazole®[4] - omeprazole® — fomepizole®[4] - Losec® — Lasix®[4] - Losec® — PROzac®[4] - Prilosec® — Pristiq®[4] - PriLOSEC® — PROzac®[4] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Antra
079739e8fd44ab0c47307530745ceb19fb3b5b52	wikidoc	Tuberculin	Tuberculin # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Tuberculin is a diagnostic agent that is FDA approved for the diagnosis of tuberculosis infection. Common adverse reactions include erythema at injection site, syncope,hypersensitivity reaction. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - TUBERSOL, Tuberculin Purified Protein Derivative (Mantoux), is indicated to aid diagnosis of tuberculosis infection (TB) in persons at increased risk of developing active disease. - The Centers for Disease Control and Prevention (CDC) have published guidelines regarding populations that would benefit from tuberculin skin testing (TST). Current recommendations can be accessed at: - Previous BCG vaccination is not a contraindication to tuberculin testing. The skin-test results of BCG vaccinated persons can be used to support or exclude the diagnosis of TB infection. However, an FDA-approved interferon gamma release assay is preferred over tuberculin skin test for persons 5 years of age and older who were previously vaccinated with BCG. # Dosage - Five (5) tuberculin units (TU) per test dose of 0.1 mL is the standard strength used for intradermal (Mantoux) testing. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Tuberculin in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Tuberculin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Tuberculin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Tuberculin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Tuberculin in pediatric patients. # Contraindications - Allergy to any component of TUBERSOL or an anaphylactic or other allergic reaction to a previous test of tuberculin PPD is a contraindication to the use of TUBERSOL. - TUBERSOL should not be administered to: - Persons who have had a severe reaction (e.g., necrosis, blistering, anaphylactic shock or ulcerations) to a previous TST, - Persons with documented active tuberculosis or a clear history of treatment for TB infection or disease, - Persons with extensive burns or eczema. # Warnings Hypersensitivity - Allergic reactions may occur following the use of tubersol even in persons with no prior history of hypersensitivity to the product components.Epinephrine injection (1:1,000) and other appropriate agents used for the control of immediate allergic reactions must be immediately available. Syncope - Syncope (fainting) can occur in association with administration of injectable medicines, including TUBERSOL. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope. # Adverse Reactions ## Clinical Trials Experience - Induration at the tubersol injection site is the expected reaction for a positive skin test. - The information pertaining to adverse events has been compiled from historical clinical studies and post-marketing experience with TUBERSOL. General disorders and administration site conditions Injection site pain, injection site pruritus and injection site discomfort. - Injection site erythema or injection site rash (without induration) occurring within 12 hours of testing. These reactions do not indicate TB infection. - Injection site hemorrhage and injection site hematoma up to three days after the administration of the test. - Injection site vesicles, injection site ulcer or injection site necrosis in highly sensitive persons. - Injection site scar as a result of strongly positive reactions. - Pyrexia Immune system disorders - Hypersensitivity, including anaphylaxis/anaphylactic reactions, angiodema, urticaria Respiratory, thoracic and mediastinal disorders - Stridor, dyspnea Skin and subcutaneous tissue disorders - Rash, generalized rash Nervous system disorders - Presyncope, syncope (including syncope associated with tonic-clonic movements and other seizure-like activity) sometimes resulting in transient loss of consciousness with injury ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tuberculin in the drug label. # Drug Interactions - Reactivity to the test may be depressed or suppressed in persons who are receiving corticosteroids or immunosuppressive agents. - Reactivity to TUBERSOL may be temporarily depressed by certain live virus vaccines (measles, mumps, rubella, oral polio, yellow fever, and varicella). If a parenteral live attenuated virus vaccine has been administered recently, tuberculin testing should be delayed for >1 month after vaccination. - When tuberculin screening is required at the same time as a measles-containing vaccine or other parenteral live attenuated virus vaccine, simultaneous administration of TUBERSOL and the vaccine at separate sites is the preferred option. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): PREGNANCY CATEGORY C - Animal reproduction studies have not been conducted with TUBERSOL. It is also not known whether TUBERSOL can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TUBERSOL should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tuberculin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tuberculin during labor and delivery. ### Nursing Mothers - It is not known whether TUBERSOL is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TUBERSOL is administered to a nursing woman. ### Pediatric Use - There is no age contraindication to tuberculin skin testing of infants. Because their immune systems are immature, many infants <6 weeks of age who are infected with M. tuberculosis do not react to tuberculin tests. ### Geriatic Use - Clinical studies of TUBERSOL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Tuberculin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tuberculin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tuberculin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tuberculin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tuberculin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tuberculin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intradermal injection - TUBERSOL is indicated for intradermal injection only. Do not inject intravenously, intramuscularly, or subcutaneously. If subcutaneous injection occurs, the test cannot be interpreted. - Inspect for extraneous particulate matter and/or discoloration before use. If these conditions exist, do not administer the product. - Use a separate syringe and needle for each injection. - The following procedure is recommended for performing the Mantoux test: - The preferred site of the test is the volar aspect of the forearm. Avoid areas on the skin that are red or swollen. Avoid visible veins. - Clean the skin site with a suitable germicide and allow the site to dry prior to injection of the antigen. - Administer the test dose (0.1 mL) of TUBERSOL with a 1 mL syringe calibrated in tenths and fitted with a short, one-quarter to one-half inch, 26 or 27 gauge needle. - Wipe the stopper of the vial with a suitable germicide and allow to dry before needle insertion. Then insert the needle gently through the stopper and draw 0.1 mL of TUBERSOL into the syringe. Avoid injection of excess air with removal of each dose so as not to over pressurize the vial and possibly cause seepage at the puncture site. - Insert the point of the needle into the most superficial layers of the skin with the needle bevel pointing upward and administer the dose by slow intradermal injection. If the intradermal injection is performed properly, a definite pale bleb will rise at the needle point, about 10 mm (⅜") in diameter. This bleb will disperse within minutes. Do not dress the site. - A drop of blood may appear at the administration site following injection. Blot the site lightly to remove the blood but avoid squeezing out the injected tuberculin test fluid. - In the event of an improperly performed injection (ie, no bleb formed), repeat the test immediately at another site, at least 2 inches from the first site and circle the second injection site as an indication that this is the site to be read. - Inform the patient of the need to return for the reading of the test by a trained health professional. Self-reading may be inaccurate and is strongly discouraged. ### Monitoring INTERPRETATION OF THE TEST - The skin test should be read by a trained health professional 48 to 72 hours after administration of TUBERSOL. Skin test sensitivity is indicated by induration only; redness should not be measured. - Measure the diameter of induration transversely to the long axis of the forearm and record the measurement in millimetres (including 0 mm). (8) The tip of a ballpoint pen, gently pushed at a 45° angle toward the site of injection, will stop at the edge of induration. - Also record presence and size (if present) of necrosis and edema, although these are not used in the interpretation of the test. Positive Reactions - Tuberculin reactivity may indicate latent infection, prior infection and/or disease with M. tuberculosis and does not necessarily indicate the presence of active tuberculous disease. Persons showing positive tuberculin reactions should be considered positive by current public health guidelines and referred for further medical evaluation.The repeated testing of uninfected persons does not sensitize them to TUBERSOL. - The significance of induration measurements in diagnosing latent TB infection must be considered in terms of the patient's history and the risk of developing active TB disease as indicated in Table 1. - A TST conversion is defined as an increase of ≥ 10 mm of induration within a 2-year period, regardless of age. - The possibility should be considered that the skin test sensitivity may also be due to a previous contact with atypical mycobacteria or previous BCG vaccination. Negative Reactions - An individual who does not show a positive reaction to 5 TU on the first test, but is suspected of being TB positive, may be retested with 5 TU.Any individual who does not show a positive reaction to an initial injection of 5 TU, or a second test with 5 TU may be considered as tuberculin negative. False Positive Reactions - False positive tuberculin reactions can occur in individuals who have been infected with other mycobacteria, including vaccination with BCG.However, a diagnosis of M. tuberculosis infection and the use of preventive therapy should be considered for any BCG-vaccinated person who has a positive TST reaction, especially if the person has been, or is, at increased risk of acquiring TB infection. False-Negative Reactions - Not all infected persons will have a delayed hypersensitivity reaction to a tuberculin test. - In those who are elderly or those who are being tested for the first time, reactions may develop slowly and may not peak until after 72 hours. - Since tuberculin sensitivity may take up to 8 weeks to develop following exposure to M. tuberculosis, persons who have a negative tuberculin test <8 weeks following possible TB exposure should be retested ≥8-10 weeks following the last known or suspected exposure. Altered Immune Status - Impaired or attenuated cell mediated immunity (CMI) can potentially cause a false negative tuberculin reaction. Many factors have been reported to cause a decreased ability to respond to the tuberculin test in the presence of tuberculous infection including viral infections (e.g., measles, mumps, chickenpox and HIV), live virus vaccinations (e.g., measles, mumps, rubella, oral polio and yellow fever), overwhelming tuberculosis, other bacterial infections, leukemia, sarcoidosis, fungal infections, metabolic derangements, low protein states, diseases affecting lymphoid organs, drugs (corticosteroids and many other immunosuppressive agents), and malignancy or stress.A TST should be deferred for patients with major viral infections or live-virus vaccination in the past month. Persons with the common cold may be tuberculin tested. - Because TST results in HIV-infected individuals are less reliable as CD4 counts decline, screening should be completed as early as possible after HIV-infection occurs. # IV Compatibility - There is limited information regarding IV Compatibility of Tuberculin in the drug label. # Overdosage - There is limited information regarding Chronic Overdose of Tuberculin in the drug label. # Pharmacology ## Mechanism of Action - The sensitization following infection with mycobacteria occurs primarily in the regional lymph nodes. Small lymphocytes (T lymphocytes) proliferate in response to the antigenic stimulus to give rise to specifically sensitized lymphocytes. After 3-8 weeks, these lymphocytes enter the blood stream and circulate for years. (7) Subsequent restimulation of these sensitized lymphocytes with the same or a similar antigen, such as the intradermal injection of TUBERSOL, evokes a local reaction mediated by these cells. - Characteristically, delayed hypersentitivity reactions to tuberculin begin at 5 to 6 hours, are maximal at 48 to 72 hours and subside over a period of days. The resultant immune response consists of induration due to cell infiltration and occasionally vesiculation and necrosis. Clinically, a delayed hypersensitivity reaction to tuberculin is a manifestation of previous infection with M tuberculosis or a variety of non-tuberculosis bacteria. In most cases sensitization is induced by natural mycobacterial infection or by vaccination with BCG Vaccine. ## Structure - TUBERSOL®, Tuberculin Purified Protein Derivative (Mantoux) (PPD) (1) for intradermal tuberculin testing is prepared from a large Master Batch Connaught Tuberculin (CT68) and is a cell-free purified protein fraction obtained from a human strain of Mycobacterium tuberculosis grown on a protein-free synthetic medium and inactivated.The use of a standard preparation derived from a single batch (CT68) has been adopted in order to eliminate batch to batch variation by the same manufacturer. - TUBERSOL is a clear, colorless liquid. - Before release, each successive lot is tested for potency in comparison with the US Standard Tuberculin PPD-S. - Independent studies conducted by the US Public Health Service in humans have determined the amount of CT68 in stabilized solution necessary to produce bio-equivalency with Tuberculin PPD-S (in phosphate buffer without polysorbate 80) using 5 US units (TU) Tuberculin PPD-S as the standard. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Tuberculin in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Tuberculin in the drug label. ## Nonclinical Toxicology CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY - TUBERSOL has not been evaluated for its carcinogenic or mutagenic potentials or impairment of fertility. # Clinical Studies There is limited information regarding Clinical Studies of Tuberculin in the drug label. # How Supplied - TUBERSOL, Tuberculin Purified Protein Derivative (Mantoux), bioequivalent to 5 US units (TU) PPD-S per test dose (0.1 mL) is supplied in: - 10-test vial, 1 mL. package of 1 vial, NDC No. 54868-2972-1 - 50-test vial, 5 mL. - The stopper of the vial for this product does not contain natural latex rubber. ## Storage - Store at 2° to 8°C (35° to 46°F). (21) Do not freeze. Discard product if exposed to freezing. - Protect from light. Tuberculin PPD solutions can be adversely affected by exposure to light. The product should be stored in the dark except when doses are actually being withdrawn from the vial. - A vial of TUBERSOL which has been entered and in use for 30 days should be discarded. - Do not use after expiration date. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Tuberculin in the drug label. # Precautions with Alcohol - Alcohol-Tuberculin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TUBERSOL ® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Tuberculin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Tuberculin is a diagnostic agent that is FDA approved for the diagnosis of tuberculosis infection. Common adverse reactions include erythema at injection site, syncope,hypersensitivity reaction. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - TUBERSOL, Tuberculin Purified Protein Derivative (Mantoux), is indicated to aid diagnosis of tuberculosis infection (TB) in persons at increased risk of developing active disease. - The Centers for Disease Control and Prevention (CDC) have published guidelines regarding populations that would benefit from tuberculin skin testing (TST). Current recommendations can be accessed at: - http://www.cdc.gov/tb/publications/factsheets/testing.htm. - Previous BCG vaccination is not a contraindication to tuberculin testing. The skin-test results of BCG vaccinated persons can be used to support or exclude the diagnosis of TB infection. However, an FDA-approved interferon gamma release assay is preferred over tuberculin skin test for persons 5 years of age and older who were previously vaccinated with BCG. # Dosage - Five (5) tuberculin units (TU) per test dose of 0.1 mL is the standard strength used for intradermal (Mantoux) testing. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Tuberculin in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Tuberculin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Tuberculin in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Tuberculin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Tuberculin in pediatric patients. # Contraindications - Allergy to any component of TUBERSOL or an anaphylactic or other allergic reaction to a previous test of tuberculin PPD is a contraindication to the use of TUBERSOL. - TUBERSOL should not be administered to: - Persons who have had a severe reaction (e.g., necrosis, blistering, anaphylactic shock or ulcerations) to a previous TST, - Persons with documented active tuberculosis or a clear history of treatment for TB infection or disease, - Persons with extensive burns or eczema. # Warnings Hypersensitivity - Allergic reactions may occur following the use of tubersol even in persons with no prior history of hypersensitivity to the product components.Epinephrine injection (1:1,000) and other appropriate agents used for the control of immediate allergic reactions must be immediately available. Syncope - Syncope (fainting) can occur in association with administration of injectable medicines, including TUBERSOL. Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope. # Adverse Reactions ## Clinical Trials Experience - Induration at the tubersol injection site is the expected reaction for a positive skin test. - The information pertaining to adverse events has been compiled from historical clinical studies and post-marketing experience with TUBERSOL. General disorders and administration site conditions Injection site pain, injection site pruritus and injection site discomfort. - Injection site erythema or injection site rash (without induration) occurring within 12 hours of testing. These reactions do not indicate TB infection. - Injection site hemorrhage and injection site hematoma up to three days after the administration of the test. - Injection site vesicles, injection site ulcer or injection site necrosis in highly sensitive persons. - Injection site scar as a result of strongly positive reactions. - Pyrexia Immune system disorders - Hypersensitivity, including anaphylaxis/anaphylactic reactions, angiodema, urticaria Respiratory, thoracic and mediastinal disorders - Stridor, dyspnea Skin and subcutaneous tissue disorders - Rash, generalized rash Nervous system disorders - Presyncope, syncope (including syncope associated with tonic-clonic movements and other seizure-like activity) sometimes resulting in transient loss of consciousness with injury ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Tuberculin in the drug label. # Drug Interactions - Reactivity to the test may be depressed or suppressed in persons who are receiving corticosteroids or immunosuppressive agents. - Reactivity to TUBERSOL may be temporarily depressed by certain live virus vaccines (measles, mumps, rubella, oral polio, yellow fever, and varicella). If a parenteral live attenuated virus vaccine has been administered recently, tuberculin testing should be delayed for >1 month after vaccination. - When tuberculin screening is required at the same time as a measles-containing vaccine or other parenteral live attenuated virus vaccine, simultaneous administration of TUBERSOL and the vaccine at separate sites is the preferred option. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): PREGNANCY CATEGORY C - Animal reproduction studies have not been conducted with TUBERSOL. It is also not known whether TUBERSOL can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TUBERSOL should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tuberculin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Tuberculin during labor and delivery. ### Nursing Mothers - It is not known whether TUBERSOL is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TUBERSOL is administered to a nursing woman. ### Pediatric Use - There is no age contraindication to tuberculin skin testing of infants. Because their immune systems are immature, many infants <6 weeks of age who are infected with M. tuberculosis do not react to tuberculin tests. ### Geriatic Use - Clinical studies of TUBERSOL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Tuberculin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Tuberculin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Tuberculin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Tuberculin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Tuberculin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Tuberculin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intradermal injection - TUBERSOL is indicated for intradermal injection only. Do not inject intravenously, intramuscularly, or subcutaneously. If subcutaneous injection occurs, the test cannot be interpreted. - Inspect for extraneous particulate matter and/or discoloration before use. If these conditions exist, do not administer the product. - Use a separate syringe and needle for each injection. - The following procedure is recommended for performing the Mantoux test: - The preferred site of the test is the volar aspect of the forearm. Avoid areas on the skin that are red or swollen. Avoid visible veins. - Clean the skin site with a suitable germicide and allow the site to dry prior to injection of the antigen. - Administer the test dose (0.1 mL) of TUBERSOL with a 1 mL syringe calibrated in tenths and fitted with a short, one-quarter to one-half inch, 26 or 27 gauge needle. - Wipe the stopper of the vial with a suitable germicide and allow to dry before needle insertion. Then insert the needle gently through the stopper and draw 0.1 mL of TUBERSOL into the syringe. Avoid injection of excess air with removal of each dose so as not to over pressurize the vial and possibly cause seepage at the puncture site. - Insert the point of the needle into the most superficial layers of the skin with the needle bevel pointing upward and administer the dose by slow intradermal injection. If the intradermal injection is performed properly, a definite pale bleb will rise at the needle point, about 10 mm (⅜") in diameter. This bleb will disperse within minutes. Do not dress the site. - A drop of blood may appear at the administration site following injection. Blot the site lightly to remove the blood but avoid squeezing out the injected tuberculin test fluid. - In the event of an improperly performed injection (ie, no bleb formed), repeat the test immediately at another site, at least 2 inches from the first site and circle the second injection site as an indication that this is the site to be read. - Inform the patient of the need to return for the reading of the test by a trained health professional. Self-reading may be inaccurate and is strongly discouraged. ### Monitoring INTERPRETATION OF THE TEST - The skin test should be read by a trained health professional 48 to 72 hours after administration of TUBERSOL. Skin test sensitivity is indicated by induration only; redness should not be measured. - Measure the diameter of induration transversely to the long axis of the forearm and record the measurement in millimetres (including 0 mm). (8) The tip of a ballpoint pen, gently pushed at a 45° angle toward the site of injection, will stop at the edge of induration. - Also record presence and size (if present) of necrosis and edema, although these are not used in the interpretation of the test. Positive Reactions - Tuberculin reactivity may indicate latent infection, prior infection and/or disease with M. tuberculosis and does not necessarily indicate the presence of active tuberculous disease. Persons showing positive tuberculin reactions should be considered positive by current public health guidelines and referred for further medical evaluation.The repeated testing of uninfected persons does not sensitize them to TUBERSOL. - The significance of induration measurements in diagnosing latent TB infection must be considered in terms of the patient's history and the risk of developing active TB disease as indicated in Table 1. - A TST conversion is defined as an increase of ≥ 10 mm of induration within a 2-year period, regardless of age. - The possibility should be considered that the skin test sensitivity may also be due to a previous contact with atypical mycobacteria or previous BCG vaccination. Negative Reactions - An individual who does not show a positive reaction to 5 TU on the first test, but is suspected of being TB positive, may be retested with 5 TU.Any individual who does not show a positive reaction to an initial injection of 5 TU, or a second test with 5 TU may be considered as tuberculin negative. False Positive Reactions - False positive tuberculin reactions can occur in individuals who have been infected with other mycobacteria, including vaccination with BCG.However, a diagnosis of M. tuberculosis infection and the use of preventive therapy should be considered for any BCG-vaccinated person who has a positive TST reaction, especially if the person has been, or is, at increased risk of acquiring TB infection. False-Negative Reactions - Not all infected persons will have a delayed hypersensitivity reaction to a tuberculin test. - In those who are elderly or those who are being tested for the first time, reactions may develop slowly and may not peak until after 72 hours. - Since tuberculin sensitivity may take up to 8 weeks to develop following exposure to M. tuberculosis, persons who have a negative tuberculin test <8 weeks following possible TB exposure should be retested ≥8-10 weeks following the last known or suspected exposure. Altered Immune Status - Impaired or attenuated cell mediated immunity (CMI) can potentially cause a false negative tuberculin reaction. Many factors have been reported to cause a decreased ability to respond to the tuberculin test in the presence of tuberculous infection including viral infections (e.g., measles, mumps, chickenpox and HIV), live virus vaccinations (e.g., measles, mumps, rubella, oral polio and yellow fever), overwhelming tuberculosis, other bacterial infections, leukemia, sarcoidosis, fungal infections, metabolic derangements, low protein states, diseases affecting lymphoid organs, drugs (corticosteroids and many other immunosuppressive agents), and malignancy or stress.A TST should be deferred for patients with major viral infections or live-virus vaccination in the past month. Persons with the common cold may be tuberculin tested. - Because TST results in HIV-infected individuals are less reliable as CD4 counts decline, screening should be completed as early as possible after HIV-infection occurs. # IV Compatibility - There is limited information regarding IV Compatibility of Tuberculin in the drug label. # Overdosage - There is limited information regarding Chronic Overdose of Tuberculin in the drug label. # Pharmacology ## Mechanism of Action - The sensitization following infection with mycobacteria occurs primarily in the regional lymph nodes. Small lymphocytes (T lymphocytes) proliferate in response to the antigenic stimulus to give rise to specifically sensitized lymphocytes. After 3-8 weeks, these lymphocytes enter the blood stream and circulate for years. (7) Subsequent restimulation of these sensitized lymphocytes with the same or a similar antigen, such as the intradermal injection of TUBERSOL, evokes a local reaction mediated by these cells. - Characteristically, delayed hypersentitivity reactions to tuberculin begin at 5 to 6 hours, are maximal at 48 to 72 hours and subside over a period of days. The resultant immune response consists of induration due to cell infiltration and occasionally vesiculation and necrosis. Clinically, a delayed hypersensitivity reaction to tuberculin is a manifestation of previous infection with M tuberculosis or a variety of non-tuberculosis bacteria. In most cases sensitization is induced by natural mycobacterial infection or by vaccination with BCG Vaccine. ## Structure - TUBERSOL®, Tuberculin Purified Protein Derivative (Mantoux) (PPD) (1) for intradermal tuberculin testing is prepared from a large Master Batch Connaught Tuberculin (CT68) and is a cell-free purified protein fraction obtained from a human strain of Mycobacterium tuberculosis grown on a protein-free synthetic medium and inactivated.The use of a standard preparation derived from a single batch (CT68) has been adopted in order to eliminate batch to batch variation by the same manufacturer. - TUBERSOL is a clear, colorless liquid. - Before release, each successive lot is tested for potency in comparison with the US Standard Tuberculin PPD-S. - Independent studies conducted by the US Public Health Service in humans have determined the amount of CT68 in stabilized solution necessary to produce bio-equivalency with Tuberculin PPD-S (in phosphate buffer without polysorbate 80) using 5 US units (TU) Tuberculin PPD-S as the standard. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Tuberculin in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Tuberculin in the drug label. ## Nonclinical Toxicology CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY - TUBERSOL has not been evaluated for its carcinogenic or mutagenic potentials or impairment of fertility. # Clinical Studies There is limited information regarding Clinical Studies of Tuberculin in the drug label. # How Supplied - TUBERSOL, Tuberculin Purified Protein Derivative (Mantoux), bioequivalent to 5 US units (TU) PPD-S per test dose (0.1 mL) is supplied in: - 10-test vial, 1 mL. package of 1 vial, NDC No. 54868-2972-1 - 50-test vial, 5 mL. - The stopper of the vial for this product does not contain natural latex rubber. ## Storage - Store at 2° to 8°C (35° to 46°F). (21) Do not freeze. Discard product if exposed to freezing. - Protect from light. Tuberculin PPD solutions can be adversely affected by exposure to light. The product should be stored in the dark except when doses are actually being withdrawn from the vial. - A vial of TUBERSOL which has been entered and in use for 30 days should be discarded. - Do not use after expiration date. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Tuberculin in the drug label. # Precautions with Alcohol - Alcohol-Tuberculin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TUBERSOL ®[1] # Look-Alike Drug Names - A® — B®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Aplisol
8835b561280a8cf12e46004cb346ad161cf20849	wikidoc	Hydrophobe	Hydrophobe # Overview In chemistry, hydrophobicity (from the combining form of water in Attic Greek hydro- and for fear phobos) refers to the physical property of a molecule (known as a hydrophobe) that is repelled from a mass of water . Hydrophobic molecules tend to be non-polar and thus prefer other neutral molecules and nonpolar solvents. Hydrophobic molecules in water often cluster together forming micelles. Water on hydrophobic surfaces will exhibit a high contact angle. Examples of hydrophobic molecules include the alkanes, oils, fats, and greasy substances in general. Hydrophobic materials are used for oil removal from water, the management of oil spills, and chemical separation processes to remove non-polar from polar compounds. Hydrophobic is often used interchangeably with "lipophilic". However, the two terms are not synonymous. While hydrophobic substances are usually lipophilic, there are exceptions — the silicones, for instance. # Chemical background According to thermodynamics, matter seeks to be in a low-energy state, and bonding reduces chemical energy. Water is electrically polarized, and is able to form hydrogen bonds internally, which gives it many of its unique physical properties. But, since hydrophobes are not electrically polarized, and because they are unable to form hydrogen bonds, water repels hydrophobes, in favour of bonding with itself. It is this effect that causes the hydrophobic interaction — which in itself is incorrectly named as the energetic force comes from the hydrophilic molecules. Thus the two immiscible phases (hydrophilic vs. hydrophobic) will change so that their corresponding interfacial area will be minimal. This effect can be visualized in the phenomenon called phase separation. # Superhydrophobicity Superhydrophobic materials have surfaces that are extremely difficult to wet with water contact angles in excess of 150°. Many of these very hydrophobic materials found in nature rely on Cassie's law and are biphasic on the submicrometer level with one component air. The Lotus effect is based on this principle. An example of a biomimetic superhydrophobic material in nanotechnology is nanopin film. In one study a vanadium pentoxide surface is presented that can switch reversibly between superhydrophobicity and superhydrophilicity under the influence of UV radiation. According to the study any surface can be modified to this effect by application of a suspension of rose-like V2O5 particles for instance with an inkjet printer. Once again hydrophobicity is induced by interlaminar air pockets (separated by 2.1 nm distances). The UV effect is also explained. UV light creates electron-hole pairs, with the holes reacting with lattice oxygen creating surface oxygen vacancies while the electrons reduce V5+ to V3+. The oxygen vacancies are met by water and this water absorbency by the vanadium surface makes it hydrophilic. By extended storage in the dark, water is replaced by oxygen and hydrophilicity is once again lost.	Hydrophobe Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In chemistry, hydrophobicity (from the combining form of water in Attic Greek hydro- and for fear phobos) refers to the physical property of a molecule (known as a hydrophobe) that is repelled from a mass of water [1]. Hydrophobic molecules tend to be non-polar and thus prefer other neutral molecules and nonpolar solvents. Hydrophobic molecules in water often cluster together forming micelles. Water on hydrophobic surfaces will exhibit a high contact angle. Examples of hydrophobic molecules include the alkanes, oils, fats, and greasy substances in general. Hydrophobic materials are used for oil removal from water, the management of oil spills, and chemical separation processes to remove non-polar from polar compounds. Hydrophobic is often used interchangeably with "lipophilic". However, the two terms are not synonymous. While hydrophobic substances are usually lipophilic, there are exceptions — the silicones, for instance. # Chemical background According to thermodynamics, matter seeks to be in a low-energy state, and bonding reduces chemical energy. Water is electrically polarized, and is able to form hydrogen bonds internally, which gives it many of its unique physical properties. But, since hydrophobes are not electrically polarized, and because they are unable to form hydrogen bonds, water repels hydrophobes, in favour of bonding with itself. It is this effect that causes the hydrophobic interaction — which in itself is incorrectly named as the energetic force comes from the hydrophilic molecules.[2] Thus the two immiscible phases (hydrophilic vs. hydrophobic) will change so that their corresponding interfacial area will be minimal. This effect can be visualized in the phenomenon called phase separation. # Superhydrophobicity Superhydrophobic materials have surfaces that are extremely difficult to wet with water contact angles in excess of 150°. Many of these very hydrophobic materials found in nature rely on Cassie's law and are biphasic on the submicrometer level with one component air. The Lotus effect is based on this principle. An example of a biomimetic superhydrophobic material in nanotechnology is nanopin film. In one study [3] a vanadium pentoxide surface is presented that can switch reversibly between superhydrophobicity and superhydrophilicity under the influence of UV radiation. According to the study any surface can be modified to this effect by application of a suspension of rose-like V2O5 particles for instance with an inkjet printer. Once again hydrophobicity is induced by interlaminar air pockets (separated by 2.1 nm distances). The UV effect is also explained. UV light creates electron-hole pairs, with the holes reacting with lattice oxygen creating surface oxygen vacancies while the electrons reduce V5+ to V3+. The oxygen vacancies are met by water and this water absorbency by the vanadium surface makes it hydrophilic. By extended storage in the dark, water is replaced by oxygen and hydrophilicity is once again lost.	https://www.wikidoc.org/index.php/Apolar
bbd633ca3ab4b68fa30532235e333c3ee9cede2f	wikidoc	Apple mint	Apple mint Apple mint (sometimes called woolly mint) (Mentha suaveolens; syn. M. rotundifolia; syn. Mentha macrostachya Ten.; syn. Mentha insularis Req.) is a member of the mint genus Mentha that ranges through southern and western Europe and the western Mediterranean region. It is a herbaceous, upright perennial plant that is most commonly grown as a culinary herb and/or ground cover. It typically grows to 40-100 cm tall and spreads by rhizomes to form clonal colonies. The foliage is light green, with the opposite, sessile leaves being oblong to nearly ovate, 3-5 cm long and 2-4 cm broad. They are somewhat hairy on top and downy underneath with serrated edges. Apple mint flowers in mid to late summer with light purple-pink flowers. # Cultivation and Uses An attractive herb, Apple mint is often used as an ornamental plant. It is hardy and easy to grow, preferring full-sun to lightly-shady conditions. The leaves of this plant can be used to make Apple mint jelly, as well as a flavoring in dishes such as Apple mint couscous. It is also often used to make a mint tea, as a garnish, or in salads. Pineapple mint (Mentha suaveolens 'Variegata') is a cultivar of Apple mint that has leaves which are banded with white. A hybrid derived from it is Grapefruit mint (Mentha suaveolens x piperata).	Apple mint Apple mint (sometimes called woolly mint) (Mentha suaveolens; syn. M. rotundifolia; syn. Mentha macrostachya Ten.; syn. Mentha insularis Req.[1]) is a member of the mint genus Mentha that ranges through southern and western Europe and the western Mediterranean region. It is a herbaceous, upright perennial plant that is most commonly grown as a culinary herb and/or ground cover. It typically grows to 40-100 cm tall and spreads by rhizomes to form clonal colonies. The foliage is light green, with the opposite, sessile leaves being oblong to nearly ovate, 3-5 cm long and 2-4 cm broad. They are somewhat hairy on top and downy underneath with serrated edges. Apple mint flowers in mid to late summer with light purple-pink flowers. # Cultivation and Uses An attractive herb, Apple mint is often used as an ornamental plant. It is hardy and easy to grow, preferring full-sun to lightly-shady conditions. The leaves of this plant can be used to make Apple mint jelly, as well as a flavoring in dishes such as Apple mint couscous. It is also often used to make a mint tea, as a garnish, or in salads. Pineapple mint (Mentha suaveolens 'Variegata') is a cultivar of Apple mint that has leaves which are banded with white. A hybrid derived from it is Grapefruit mint (Mentha suaveolens x piperata). # External links and References - ↑ Quattrocchi, Umberto (1947-). CRC World dictionary of plant names: Common names, Scientific Names, Eponyms, Sonyonyms, and Etymology. III M-Q. CRC Press. p. 1659. Check date values in: \|year= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - Pink, A. (2004). Gardening for the Million. Project Gutenberg Literary Archive Foundation. Check date values in: \|year= (help); External link in \|title= (help) - Natural History Museum: Mentha suaveolens - Plants for a Future: Mentha suaveolens Template:Lamiales-stub nl:Witte munt	https://www.wikidoc.org/index.php/Apple_mint
39a94bce60a9770f8560f84ac6d8ad97a8e8f75a	wikidoc	Apremilast	Apremilast - OTEZLA is indicated for the treatment of adult patients with active psoriatic arthritis. - OTEZLA is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. # Dosage - The recommended initial dosage titration of OTEZLA from Day 1 to Day 5 is shown in TABLE 1. Following the 5-day titration, the recommended maintenance dosage is 30 mg twice daily taken orally starting on Day 6. This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy. - OTEZLA can be administered without regard to meals. Do not crush, split, or chew the tablets. - OTEZLA dosage should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance (CLcr) of less than 30 mL per minute estimated by the Cockcroft–Gault equation). For initial dosage titration in this group, it is recommended that OTEZLA be titrated using only the AM schedule listed in TABLE 1 and the PM doses be skipped. # DOSAGE FORMS AND STRENGTHS - OTEZLA is available as diamond shaped, film coated tablets in the following dosage strengths: - Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. - During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects. - During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects(0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide. - During the controlled period of the studies in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo. - During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo. - Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials of similar design in adult patients with active psoriatic arthritis. Across the 3 studies, there were 1493 patients randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days. Placebo patients whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA patients remained on their initial treatment. Patients ranged in age from 18 to 83 years, with an overall median age of 51 years. - The majority of the most common adverse reactions presented in TABLE 2 occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients. - Other adverse reactions reported in patients on OTEZLA in clinical studies including extension studies: - Immune system disorders: Hypersensitivity - Investigations: Weight decrease - Gastrointestinal Disorders: Frequent bowel movement, gastroesophageal reflux disease, dyspepsia - Metabolism and Nutrition Disorders: Decreased appetite - Nervous System Disorders: Migraine - Respiratory, Thoracic, and Mediastinal Disorders: Cough - Skin and Subcutaneous Tissue Disorders: Rash - 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction. - The safety of OTEZLA® was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days. Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years. - Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for subjects treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated subjects. - Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA. - Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy - Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972. - Adequate and well-controlled studies with OTEZLA have not been conducted in pregnant women. In animal embryo-fetal development studies, the administration of apremilast to cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures 2.1-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. In mice, there were no apremilast induced malformations up to exposures 4.0-times the MRHD. The incidences of malformations and pregnancy loss in human pregnancies have not been established for OTEZLA. However, all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - The effects of OTEZLA on labor and delivery in pregnant women are unknown. In mice, dystocia was noted at doses corresponding to ≥4.0-times the MRHD (on an AUC basis at doses ≥80 mg/kg/day) of apremilast. - Monkey embryo-fetal development: In an embryo-fetal developmental study, cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1000 mg/kg/day during the period of organogenesis (gestation Days 20 through 50). There was a dose-related increase in spontaneous abortions, with most abortions occurring during weeks 3 to 4 of dosing in the first trimester, at doses approximately 2.1-times the MRHD and greater (on an AUC basis at doses ≥50 mg/kg/day). No abortifacient effects were observed at a dose approximately 1.4-times the MRHD (on an AUC basis at a dose of 20 mg/kg/day). Although, there was no evidence for a teratogenic effect at doses of 20 mg/kg/day and greater when examined at day 100, aborted fetuses were not examined. - Mouse embryo-fetal development: In an embryo-fetal development study, apremilast was administered at doses of 250, 500, or 750 mg/kg/day to dams during organogenesis (gestation Day 6 through 15). In a combined fertility and embryo-fetal development study, apremilast was administered at doses of 10, 20, 40 or 80 mg/kg/day starting 15 days before cohabitation and continuing through gestation Day 15. No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in postimplantation loss at doses corresponding to a systemic exposure of 2.3-times the MRHD and greater (≥20 mg/kg/day). At doses of ≥20 mg/kg/day skeletal variations included incomplete ossification sites of tarsals, skull, sternebra, and vertebrae. No effects were observed at a dose approximately 1.3-times the MRHD (10 mg/kg/day). - Mouse pre- and postnatal development: In a pre- and postnatal study in mice, apremilast was administered to pregnant female mice at doses of 10, 80, or 300 mg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on day 21. Dystocia, reduced viability, and reduced birth weights occurred at doses corresponding to ≥4.0-times the MRHD (on an AUC basis at doses ≥80 mg/kg/day). No adverse effects occurred at a dose 1.3-times the MRHD (10 mg/kg/day). There was no evidence for functional impairment of physical development, behavior, learning ability, immune competence, or fertility in the offspring at doses up to 7.5-times the MRHD (on an AUC basis at a dose of 300 mg/kg/day). - Of the 1257 subjects who enrolled in two placebo-controlled psoriasis trials (PSOR 1 and PSOR 2), a total of 108 psoriasis subjects were 65 years of age and older, including 9 subjects who were 75 years of age and older. No overall differences were observed in the efficacy and safety in elderly subjects ≥65 years of age and younger adult subjects <65 years of age in the clinical trials. - The chemical structure is: - Apremilast when taken orally is absorbed with an absolute bioavailability of ~73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of ~2.5 hours. Co-administration with food does not alter the extent of absorption of apremilast. - Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L. - Following oral administration in humans, apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. - The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively. - Hepatic Impairment: The pharmacokinetics of apremilast is not affected by moderate or severe hepatic impairment. - Renal Impairment: In 8 subjects with severe renal impairment administered a single dose of 30 mg apremilast, the AUC and Cmax of apremilast increased by approximately 88% and 42%, respectively. - Age: A single oral dose of 30-mg apremilast was studied in young adults and elderly healthy subjects. The apremilast exposure in elderly subjects (65 to 85 years of age) was about 13% higher in AUC and about 6% higher in Cmax than in young subjects (18 to 55 years of age). - Gender: In pharmacokinetic studies in healthy volunteers, the extent of exposure in females was about 31% higher and Cmax was about 8% higher than that in male subjects. - Race and Ethnicity: The pharmacokinetics of apremilast in Chinese and Japanese healthy male subjects is comparable to that in Caucasian healthy male subjects. In addition, apremilast exposure is similar among Hispanic Caucasians, non-Hispanic Caucasians, and African Americans. - In vitro data: Apremilast is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and not an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4. Apremilast is a substrate, but not an inhibitor of P-glycoprotein (P-gp) and is not a substrate or an inhibitor of organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP). - Drug interaction studies were performed with apremilast and CYP3A4 substrates (oral contraceptive containing ethinyl estradiol and norgestimate), CYP3A and P-gp inhibitor (ketoconazole), CYP450 inducer (rifampin) and frequently co-administered drug in this patient population (methotrexate). - No significant pharmacokinetic interactions were observed when 30-mg oral apremilast was administered with either oral contraceptive, ketoconazole, or methotrexate. Co-administration of the CYP450 inducer rifampin (600 mg once daily for 15 days) with a single oral dose of 30-mg apremilast resulted in reduction of apremilast AUC and Cmax by 72% and 43%, respectively - Long-term studies were conducted in mice and rats with apremilast to evaluate its carcinogenic potential. No evidence of apremilast-induced tumors was observed in mice at oral doses up to 8.8-times the Maximum Recommended Human Dose (MRHD) on an AUC basis (1000 mg/kg/day) or in rats at oral doses up to approximately 0.08- and 1.1-times the MRHD, (20 mg/kg/day in males and 3 mg/kg/day in females, respectively). - Apremilast tested negative in the Ames assay, in vitro chromosome aberration assay of human peripheral blood lymphocytes, and the in vivo mouse micronucleus assay. - In a fertility study of male mice, apremilast at oral doses up to approximately 3-times the MRHD based on AUC (up to 50 mg/kg/day) produced no effects on male fertility. In a fertility study of female mice, apremilast was administered at oral doses of 10, 20, 40, or 80 mg/kg/day. At doses ≥1.8-times the MRHD (≥20 mg/kg/day), estrous cycles were prolonged, due to lengthening of diestrus which resulted in a longer interval until mating. Mice that became pregnant at doses of 20 mg/kg/day and greater also had increased incidences of early postimplantation losses. There was no effect of apremilast approximately 1.0-times the MRHD (10 mg/kg/day). - The safety and efficacy of OTEZLA was evaluated in 3 multi-center, randomized, double-blind, placebo-controlled trials (Studies PsA-1, PsA-2, and PsA-3) of similar design. A total of 1493 adult patients with active PsA (≥3 swollen joints and ≥3 tender joints) despite prior or current treatment with disease-modifying antirheumatic drug (DMARD) therapy were randomized. Patients enrolled in these studies had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skin lesion of at least 2 cm in diameter was required in Study PsA- 3. Previous treatment with a biologic, including TNF-blockers was allowed (up to 10% could be TNF-blocker therapeutic failures). Across the 3 studies, patients were randomly assigned to placebo (n=496), OTEZLA 20 mg (n=500), or OTEZLA 30 mg (n=497) given orally twice daily. Titration was used over the first 5 days . Patients were allowed to receive stable doses of concomitant methotrexate , sulfasalazine , leflunomide , low dose oral corticosteroids (equivalent to ≤10 mg of prednisone a day), and/or nonsteroidal anti-inflammatory drugs (NSAIDs) during the trial. Treatment assignments were stratified based on small-molecule DMARD use at baseline in Studies PsA-1, PsA-2 and PsA-3. There was an additional stratification of BSA >3% with psoriasis in study PsA-3. The patients who were therapeutic failures of >3 agents for PsA (small molecules or biologics), or >1 biologic TNF blocker were excluded. - The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at Week 16. Placebo-controlled efficacy data were collected and analyzed through Week 24. Patients whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at Week 16. Placebo non-responders were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily following the titration schema. OTEZLA patients remained on their initial treatment. At Week 24, all remaining placebo patients were re-randomized to either 20 mg twice daily or 30 mg twice daily. - Patients with subtypes of PsA were enrolled across the 3 studies, including symmetric polyarthritis (62.0%), asymmetric oligoarthritis (27.0%), distal interphalangeal (DIP) joint arthritis (6.0%), arthritis mutilans (3.0%), and predominant spondylitis (2.1%). The median duration of PsA disease was 5 years. Patients received concomitant therapy with at least one DMARD (65.0%), MTX (55.0%), SSZ (9.0%), LEF (7.0%), low dose oral corticosteroids (14.0%), and NSAIDs (71.0%). Prior treatment with small-molecule DMARDs only was reported in 76.0% of patients and prior treatment with biologic DMARDs was reported in 22.0% of patients, which includes 9.0% who had failed prior biologic DMARD treatment. - The percent of patients achieving ACR 20, 50 and 70 responses in Studies PsA-1, PsA-2, and PsA-3 are presented in TABLE 4 below. OTEZLA ± DMARDs, compared with Placebo ± DMARDs resulted in a greater improvement in signs and symptoms of psoriatic arthritis as demonstrated by the proportion of patients with an ACR 20 response at Week 16. - OTEZLA 30 mg twice daily resulted in improvement for each ACR component, compared to placebo at Week 16 in Study PsA-1 (TABLE 5). Consistent results were observed in Studies PsA-2 and PsA-3. - Treatment with OTEZLA resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis. - Physical Function Response - OTEZLA 30 mg twice daily demonstrated a greater improvement compared to placebo in mean change from baseline for the Health Assessment Questionnaire Disability Index (HAQ-DI) score at Week 16 in Study PsA-1. The proportions of HAQ-DI responders (≥0.3 improvement from baseline) at Week 16 for the OTEZLA 30 mg twice daily group were 38%, compared to 27%, for the placebo group in Study PsA-1. Consistent results were observed in Studies PsA-2 and PsA-3. - Two multicenter, randomized, double-blind, placebo-controlled trials (Studies PSOR-1 and PSOR-2) enrolled a total of 1257 subjects 18 years of age and older with moderate to severe plaque psoriasis . Subjects were allowed to use low-potency topical corticosteroids on the face, axilla and groin. Subjects with scalp psoriasis were allowed to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions. - Study PSOR-1 enrolled 844 subjects and Study PSOR-2 enrolled 413 subjects. In both studies, subjects were randomized 2:1 to OTEZLA 30 mg BID or placebo for 16 weeks. Both studies assessed the proportion of subjects who achieved PASI-75 at Week 16 and the proportion of subjects who achieved a sPGA score of clear (0) or almost clear (1) at Week 16. Across both studies, subjects ranged in age from 18 to 83 years, with an overall median age of 46 years. The mean baseline BSA involvement was 25.19% (median 21.0%), the mean baseline PASI score was 19.07 (median 16.80), and the proportion of subjects with sPGA score of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. Approximately 30% of all subjects had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. Approximately one-third of subjects had not received prior phototherapy, conventional systemic nor biologic therapy. A total of 18% of subjects had a history of psoriatic arthritis. - The proportion of subjects who achieved PASI -75 responses, and sPGA score of clear (0) or almost clear (1), are presented in TABLE 6. - The median time to loss of PASI-75 response among the subjects re-randomized to placebo at Week 32 during the Randomized Treatment Withdrawal Phase was 5.1 weeks. - Tablets are supplied in the following strengths and package configurations # Ingredients and Appearance - Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. . - Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered . - The use of strong cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended. - Instruct patients to take OTEZLA only as prescribed. - Advise patients OTEZLA can be taken with or without food. - Advise patients that the tablets should not be crushed, split, or chewed. - Advise patients about the side effects associated with OTEZLA - ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 "Otezla (aprelimast) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 March 2014..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ "Apremilast".	Apremilast - OTEZLA is indicated for the treatment of adult patients with active psoriatic arthritis. - OTEZLA is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. ### Dosage - The recommended initial dosage titration of OTEZLA from Day 1 to Day 5 is shown in TABLE 1. Following the 5-day titration, the recommended maintenance dosage is 30 mg twice daily taken orally starting on Day 6. This titration is intended to reduce the gastrointestinal symptoms associated with initial therapy. - OTEZLA can be administered without regard to meals. Do not crush, split, or chew the tablets. - OTEZLA dosage should be reduced to 30 mg once daily in patients with severe renal impairment (creatinine clearance (CLcr) of less than 30 mL per minute estimated by the Cockcroft–Gault equation). For initial dosage titration in this group, it is recommended that OTEZLA be titrated using only the AM schedule listed in TABLE 1 and the PM doses be skipped. ### DOSAGE FORMS AND STRENGTHS - OTEZLA is available as diamond shaped, film coated tablets in the following dosage strengths: - Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. - During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects. - During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects(0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide. - During the controlled period of the studies in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo. - During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo. - Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials [Studies PsA-1, PsA-2, and PsA-3] of similar design in adult patients with active psoriatic arthritis. Across the 3 studies, there were 1493 patients randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days. Placebo patients whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA patients remained on their initial treatment. Patients ranged in age from 18 to 83 years, with an overall median age of 51 years. - The majority of the most common adverse reactions presented in TABLE 2 occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients. - Other adverse reactions reported in patients on OTEZLA in clinical studies including extension studies: - Immune system disorders: Hypersensitivity - Investigations: Weight decrease - Gastrointestinal Disorders: Frequent bowel movement, gastroesophageal reflux disease, dyspepsia - Metabolism and Nutrition Disorders: Decreased appetite - Nervous System Disorders: Migraine - Respiratory, Thoracic, and Mediastinal Disorders: Cough - Skin and Subcutaneous Tissue Disorders: Rash - 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction. - The safety of OTEZLA® was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days. Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years. - Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for subjects treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated subjects. - Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA. - Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy - Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972. - Adequate and well-controlled studies with OTEZLA have not been conducted in pregnant women. In animal embryo-fetal development studies, the administration of apremilast to cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures 2.1-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. In mice, there were no apremilast induced malformations up to exposures 4.0-times the MRHD. The incidences of malformations and pregnancy loss in human pregnancies have not been established for OTEZLA. However, all pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - The effects of OTEZLA on labor and delivery in pregnant women are unknown. In mice, dystocia was noted at doses corresponding to ≥4.0-times the MRHD (on an AUC basis at doses ≥80 mg/kg/day) of apremilast. - Monkey embryo-fetal development: In an embryo-fetal developmental study, cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1000 mg/kg/day during the period of organogenesis (gestation Days 20 through 50). There was a dose-related increase in spontaneous abortions, with most abortions occurring during weeks 3 to 4 of dosing in the first trimester, at doses approximately 2.1-times the MRHD and greater (on an AUC basis at doses ≥50 mg/kg/day). No abortifacient effects were observed at a dose approximately 1.4-times the MRHD (on an AUC basis at a dose of 20 mg/kg/day). Although, there was no evidence for a teratogenic effect at doses of 20 mg/kg/day and greater when examined at day 100, aborted fetuses were not examined. - Mouse embryo-fetal development: In an embryo-fetal development study, apremilast was administered at doses of 250, 500, or 750 mg/kg/day to dams during organogenesis (gestation Day 6 through 15). In a combined fertility and embryo-fetal development study, apremilast was administered at doses of 10, 20, 40 or 80 mg/kg/day starting 15 days before cohabitation and continuing through gestation Day 15. No teratogenic findings attributed to apremilast were observed in either study; however, there was an increase in postimplantation loss at doses corresponding to a systemic exposure of 2.3-times the MRHD and greater (≥20 mg/kg/day). At doses of ≥20 mg/kg/day skeletal variations included incomplete ossification sites of tarsals, skull, sternebra, and vertebrae. No effects were observed at a dose approximately 1.3-times the MRHD (10 mg/kg/day). - Mouse pre- and postnatal development: In a pre- and postnatal study in mice, apremilast was administered to pregnant female mice at doses of 10, 80, or 300 mg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on day 21. Dystocia, reduced viability, and reduced birth weights occurred at doses corresponding to ≥4.0-times the MRHD (on an AUC basis at doses ≥80 mg/kg/day). No adverse effects occurred at a dose 1.3-times the MRHD (10 mg/kg/day). There was no evidence for functional impairment of physical development, behavior, learning ability, immune competence, or fertility in the offspring at doses up to 7.5-times the MRHD (on an AUC basis at a dose of 300 mg/kg/day). - Of the 1257 subjects who enrolled in two placebo-controlled psoriasis trials (PSOR 1 and PSOR 2), a total of 108 psoriasis subjects were 65 years of age and older, including 9 subjects who were 75 years of age and older. No overall differences were observed in the efficacy and safety in elderly subjects ≥65 years of age and younger adult subjects <65 years of age in the clinical trials. - The chemical structure is: - Apremilast when taken orally is absorbed with an absolute bioavailability of ~73%, with peak plasma concentrations (Cmax) occurring at a median time (tmax) of ~2.5 hours. Co-administration with food does not alter the extent of absorption of apremilast. - Human plasma protein binding of apremilast is approximately 68%. Mean apparent volume of distribution (Vd) is 87 L. - Following oral administration in humans, apremilast is a major circulating component (45%) followed by inactive metabolite M12 (39%), a glucuronide conjugate of O-demethylated apremilast. It is extensively metabolized in humans with up to 23 metabolites identified in plasma, urine and feces. Apremilast is metabolized by both cytochrome (CYP) oxidative metabolism with subsequent glucuronidation and non-CYP mediated hydrolysis. In vitro, CYP metabolism of apremilast is primarily mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. - The plasma clearance of apremilast is about 10 L/hr in healthy subjects, with a terminal elimination half-life of approximately 6-9 hours. Following oral administration of radio-labeled apremilast, about 58% and 39% of the radioactivity is recovered in urine and feces, respectively, with about 3% and 7% of the radioactive dose recovered as apremilast in urine and feces, respectively. - Hepatic Impairment: The pharmacokinetics of apremilast is not affected by moderate or severe hepatic impairment. - Renal Impairment: In 8 subjects with severe renal impairment administered a single dose of 30 mg apremilast, the AUC and Cmax of apremilast increased by approximately 88% and 42%, respectively. - Age: A single oral dose of 30-mg apremilast was studied in young adults and elderly healthy subjects. The apremilast exposure in elderly subjects (65 to 85 years of age) was about 13% higher in AUC and about 6% higher in Cmax than in young subjects (18 to 55 years of age). - Gender: In pharmacokinetic studies in healthy volunteers, the extent of exposure in females was about 31% higher and Cmax was about 8% higher than that in male subjects. - Race and Ethnicity: The pharmacokinetics of apremilast in Chinese and Japanese healthy male subjects is comparable to that in Caucasian healthy male subjects. In addition, apremilast exposure is similar among Hispanic Caucasians, non-Hispanic Caucasians, and African Americans. - In vitro data: Apremilast is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and not an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4. Apremilast is a substrate, but not an inhibitor of P-glycoprotein (P-gp) and is not a substrate or an inhibitor of organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1 and OATP1B3, or breast cancer resistance protein (BCRP). - Drug interaction studies were performed with apremilast and CYP3A4 substrates (oral contraceptive containing ethinyl estradiol and norgestimate), CYP3A and P-gp inhibitor (ketoconazole), CYP450 inducer (rifampin) and frequently co-administered drug in this patient population (methotrexate). - No significant pharmacokinetic interactions were observed when 30-mg oral apremilast was administered with either oral contraceptive, ketoconazole, or methotrexate. Co-administration of the CYP450 inducer rifampin (600 mg once daily for 15 days) with a single oral dose of 30-mg apremilast resulted in reduction of apremilast AUC and Cmax by 72% and 43%, respectively - Long-term studies were conducted in mice and rats with apremilast to evaluate its carcinogenic potential. No evidence of apremilast-induced tumors was observed in mice at oral doses up to 8.8-times the Maximum Recommended Human Dose (MRHD) on an AUC basis (1000 mg/kg/day) or in rats at oral doses up to approximately 0.08- and 1.1-times the MRHD, (20 mg/kg/day in males and 3 mg/kg/day in females, respectively). - Apremilast tested negative in the Ames assay, in vitro chromosome aberration assay of human peripheral blood lymphocytes, and the in vivo mouse micronucleus assay. - In a fertility study of male mice, apremilast at oral doses up to approximately 3-times the MRHD based on AUC (up to 50 mg/kg/day) produced no effects on male fertility. In a fertility study of female mice, apremilast was administered at oral doses of 10, 20, 40, or 80 mg/kg/day. At doses ≥1.8-times the MRHD (≥20 mg/kg/day), estrous cycles were prolonged, due to lengthening of diestrus which resulted in a longer interval until mating. Mice that became pregnant at doses of 20 mg/kg/day and greater also had increased incidences of early postimplantation losses. There was no effect of apremilast approximately 1.0-times the MRHD (10 mg/kg/day). - The safety and efficacy of OTEZLA was evaluated in 3 multi-center, randomized, double-blind, placebo-controlled trials (Studies PsA-1, PsA-2, and PsA-3) of similar design. A total of 1493 adult patients with active PsA (≥3 swollen joints and ≥3 tender joints) despite prior or current treatment with disease-modifying antirheumatic drug (DMARD) therapy were randomized. Patients enrolled in these studies had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skin lesion of at least 2 cm in diameter was required in Study PsA- 3. Previous treatment with a biologic, including TNF-blockers was allowed (up to 10% could be TNF-blocker therapeutic failures). Across the 3 studies, patients were randomly assigned to placebo (n=496), OTEZLA 20 mg (n=500), or OTEZLA 30 mg (n=497) given orally twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1)]. Patients were allowed to receive stable doses of concomitant methotrexate [MTX (≤25 mg/week)], sulfasalazine [SSZ (≤2 g/day)], leflunomide [LEF (≤20 mg/day)], low dose oral corticosteroids (equivalent to ≤10 mg of prednisone a day), and/or nonsteroidal anti-inflammatory drugs (NSAIDs) during the trial. Treatment assignments were stratified based on small-molecule DMARD use at baseline in Studies PsA-1, PsA-2 and PsA-3. There was an additional stratification of BSA >3% with psoriasis in study PsA-3. The patients who were therapeutic failures of >3 agents for PsA (small molecules or biologics), or >1 biologic TNF blocker were excluded. - The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at Week 16. Placebo-controlled efficacy data were collected and analyzed through Week 24. Patients whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at Week 16. Placebo non-responders were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily following the titration schema. OTEZLA patients remained on their initial treatment. At Week 24, all remaining placebo patients were re-randomized to either 20 mg twice daily or 30 mg twice daily. - Patients with subtypes of PsA were enrolled across the 3 studies, including symmetric polyarthritis (62.0%), asymmetric oligoarthritis (27.0%), distal interphalangeal (DIP) joint arthritis (6.0%), arthritis mutilans (3.0%), and predominant spondylitis (2.1%). The median duration of PsA disease was 5 years. Patients received concomitant therapy with at least one DMARD (65.0%), MTX (55.0%), SSZ (9.0%), LEF (7.0%), low dose oral corticosteroids (14.0%), and NSAIDs (71.0%). Prior treatment with small-molecule DMARDs only was reported in 76.0% of patients and prior treatment with biologic DMARDs was reported in 22.0% of patients, which includes 9.0% who had failed prior biologic DMARD treatment. - The percent of patients achieving ACR 20, 50 and 70 responses in Studies PsA-1, PsA-2, and PsA-3 are presented in TABLE 4 below. OTEZLA ± DMARDs, compared with Placebo ± DMARDs resulted in a greater improvement in signs and symptoms of psoriatic arthritis as demonstrated by the proportion of patients with an ACR 20 response at Week 16. - OTEZLA 30 mg twice daily resulted in improvement for each ACR component, compared to placebo at Week 16 in Study PsA-1 (TABLE 5). Consistent results were observed in Studies PsA-2 and PsA-3. - Treatment with OTEZLA resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis. - Physical Function Response - OTEZLA 30 mg twice daily demonstrated a greater improvement compared to placebo in mean change from baseline for the Health Assessment Questionnaire Disability Index (HAQ-DI) score at Week 16 [-0.244 vs. -0.086, respectively; 95% CI for the difference was (-0.26, -0.06)] in Study PsA-1. The proportions of HAQ-DI responders (≥0.3 improvement from baseline) at Week 16 for the OTEZLA 30 mg twice daily group were 38%, compared to 27%, for the placebo group in Study PsA-1. Consistent results were observed in Studies PsA-2 and PsA-3. - Two multicenter, randomized, double-blind, placebo-controlled trials (Studies PSOR-1 and PSOR-2) enrolled a total of 1257 subjects 18 years of age and older with moderate to severe plaque psoriasis [body surface area (BSA) involvement of ≥10%, static Physician Global Assessment (sPGA) of ≥3 (moderate or severe disease), Psoriasis Area and Severity Index (PASI) score ≥12, candidates for phototherapy or systemic therapy]. Subjects were allowed to use low-potency topical corticosteroids on the face, axilla and groin. Subjects with scalp psoriasis were allowed to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions. - Study PSOR-1 enrolled 844 subjects and Study PSOR-2 enrolled 413 subjects. In both studies, subjects were randomized 2:1 to OTEZLA 30 mg BID or placebo for 16 weeks. Both studies assessed the proportion of subjects who achieved PASI-75 at Week 16 and the proportion of subjects who achieved a sPGA score of clear (0) or almost clear (1) at Week 16. Across both studies, subjects ranged in age from 18 to 83 years, with an overall median age of 46 years. The mean baseline BSA involvement was 25.19% (median 21.0%), the mean baseline PASI score was 19.07 (median 16.80), and the proportion of subjects with sPGA score of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. Approximately 30% of all subjects had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. Approximately one-third of subjects had not received prior phototherapy, conventional systemic nor biologic therapy. A total of 18% of subjects had a history of psoriatic arthritis. - The proportion of subjects who achieved PASI -75 responses, and sPGA score of clear (0) or almost clear (1), are presented in TABLE 6. - The median time to loss of PASI-75 response among the subjects re-randomized to placebo at Week 32 during the Randomized Treatment Withdrawal Phase was 5.1 weeks. - Tablets are supplied in the following strengths and package configurations ### Ingredients and Appearance - Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. [See Warnings and Precautions (5.1)]. - Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered [see Warnings and Precautions (5.2)]. - The use of strong cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended. - Instruct patients to take OTEZLA only as prescribed. - Advise patients OTEZLA can be taken with or without food. - Advise patients that the tablets should not be crushed, split, or chewed. - Advise patients about the side effects associated with OTEZLA - ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 "Otezla (aprelimast) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 March 2014..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ "Apremilast".	https://www.wikidoc.org/index.php/Apremilast
02fcabe9e8ddca234632ee0af5772cf47557b730	wikidoc	Aprepitant	Aprepitant # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Aprepitant is an antiemetic, neurokinin-1 receptor antagonist that is FDA approved for the prophylaxis of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin and nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). Its also, indicated for the prevention of postoperative nausea and vomiting (PONV). Common adverse reactions include alopecia, anorexia, asthenia/fatigue, constipation, diarrhea, headache, hiccups, nausea, hypotension, pruritus, pyrexia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Capsules of Aprepitant (aprepitant) are given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of Aprepitant is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3. - Aprepitant may be taken with or without food. - Aprepitant (fosaprepitant dimeglumine) for Injection (115 mg) is a prodrug of aprepitant and may be substituted for oral Aprepitant (125 mg), 30 minutes prior to chemotherapy, on Day 1 only of the CINV regimen as an intravenous infusion administered over 15 minutes. In clinical studies with Aprepitant, the following regimen was used for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy: In a clinical study with Aprepitant, the following regimen was used for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy: - The recommended oral dosage of Aprepitant is 40 mg within 3 hours prior to induction of anesthesia. Aprepitant may be taken with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Aprepitant (patient information) in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Aprepitant (patient information) in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Aprepitant FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Aprepitant (patient information) in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Aprepitant (patient information) in pediatric patients. # Contraindications - Aprepitant is contraindicated in patients who are hypersensitive to any component of the product. Aprepitant is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). Aprepitant should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. # Warnings - Aprepitant (aprepitant), a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125 mg/80 mg regimen, could result in elevated plasma concentrations of these concomitant medications. - Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. - When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When Aprepitant is used concomitantly with medications that induce CYP3A4 activity aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of Aprepitant. - Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, Aprepitant (125 mg/80 mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. - In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when Aprepitant (125 mg/80 mg regimen) was co-administered. - Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. - Coadministration of Aprepitant with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of Aprepitant with each chemotherapy cycle, or following administration of a single 40 mg dose of Aprepitant for the prevention of postoperative nausea and vomiting. - Upon coadministration with Aprepitant, the efficacy of hormonal contraceptives during and for 28 days following the last dose of Aprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with Aprepitant and for 1 month following the last dose of Aprepitant. - There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when Aprepitant is administered in these patients. - Chronic continuous use of Aprepitant for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use. # Adverse Reactions ## Clinical Trials Experience - In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. Aprepitant was given in combination with ondansetron and dexamethasone. - In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Table 1 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3%. - In a combined analysis of these two studies, isolated cases of serious adverse experiences were similar in the two treatment groups. ### Highly and Moderately Emetogenic Chemotherapy The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen in either HEC or MEC studies: - Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection. - Neoplasms benign, malignant and unspecified (including cysts and polyps): malignant neoplasm, non-small cell lung carcinoma. - Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia. - Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia. - Psychiatric disorders: anxiety disorder, confusion, depression. - Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor. - Eye disorders: conjunctivitis. - Cardiac disorders: myocardial infarction, palpitations, tachycardia. - Vascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotension. - Respiratory, thoracic and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance. - Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased. - Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash. - Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia. - Renal and urinary disorders: dysuria, renal insufficiency. - Reproductive system and breast disorders: pelvic pain. - General disorders and administrative site conditions: edema, malaise, pain, rigors. - Investigations: weight loss. - Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study. ### Laboratory Adverse Experiences Table 3 shows the percent of patients with laboratory adverse experiences reported at an incidence ≥3% in patients receiving highly emetogenic chemotherapy - The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia. The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1. - In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron IV. - Clinical adverse experiences were reported in approximately 60% of patients treated with 40 mg aprepitant compared with approximately 64% of patients treated with 4 mg ondansetron IV. Table 4 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3% of the combined studies. The following additional clinical adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant: - Infections and infestations: postoperative infection - Metabolism and nutrition disorders: hypokalemia, hypovolemia. - Nervous system disorders: dizziness, hypoesthesia, syncope. - Vascular disorders: hematoma - Respiratory, thoracic and mediastinal disorders: dyspnea, hypoxia, respiratory depression. - Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia. - Skin and subcutaneous tissue disorders: urticaria - General disorders and administrative site conditions: hypothermia, pain. - Investigations: hypotension - Injury, poisoning and procedural complications: operative hemorrhage, wound dehiscence. Other adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included: - Nervous system disorders: dysarthria, sensory disturbance. - Eye disorders: miosis, visual acuity reduced. - Respiratory, thoracic and mediastinal disorders: wheezing - Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort. There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40 mg aprepitant. ### Laboratory Adverse Experiences - One laboratory adverse experience, hemoglobin decreased (40 mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia. - The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present. The adverse experience of ALT increased occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%). ### Other Studies - In addition, two serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus. - Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study. ## Postmarketing Experience The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug. - Skin and subcutaneous tissue disorders: pruritus, rash, urticaria. - Immune system disorders: hypersensitivity reactions including anaphylactic reactions. # Drug Interactions - Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect. - As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg). - In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). - Dexamethasone: Aprepitant, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and Aprepitant when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with Aprepitant (125 mg/80 mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without Aprepitant. The daily dose of dexamethasone administered in clinical chemotherapy induced nausea and vomiting studies with Aprepitant reflects an approximate 50% reduction of the dose of dexamethasone. A single dose of Aprepitant (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended. - Methylprednisolone: Aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with Aprepitant (125 mg/80 mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without Aprepitant Although the concomitant administration of methylprednisolone with the single 40 mg dose of aprepitant has not been studied, a single 40 mg dose of Aprepitant produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended. - Docetaxel: In a pharmacokinetic study, Aprepitant (125 mg/80 mg regimen) did not influence the pharmacokinetics of docetaxel. - Vinorelbine: In a pharmacokinetic study, Aprepitant (125 mg/80 mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree. - Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of Aprepitant with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs. - A single 125-mg dose of Aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of Aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with Aprepitant In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of Aprepitant with each chemotherapy cycle, or following administration of a single 40 mg dose of Aprepitant for the prevention of postoperative nausea and vomiting. - Aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of Aprepitant and on Days 4, 8, and 15. - Aprepitant, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of Aprepitant 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important. - Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%. - In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and Aprepitant was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of Aprepitant on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21. - In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and Aprepitant 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with Aprepitant 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone. - The coadministration of Aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of Aprepitant. Alternative or back-up methods of contraception should be used during treatment with Aprepitant and for 1 month following the last dose of Aprepitant. - Aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of Aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with Aprepitant (125 mg/80 mg). A single dose of Aprepitant (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with Aprepitant 40 mg; this effect was not considered clinically important. - In another study with intravenous administration of midazolam, Aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of Aprepitant and on Days 4, 8, and 15. Aprepitant increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of Aprepitant on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline. - An additional study was completed with intravenous administration of midazolam and Aprepitant. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of Aprepitant 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (e.g., elderly patients) and degree of monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with Aprepitant for the chemotherapy induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3). - Aprepitant is a substrate for CYP3A4; therefore, coadministration of Aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of Aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. - Aprepitant is a substrate for CYP3A4; therefore, coadministration of Aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of Aprepitant. - When a single 125-mg dose of Aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of Aprepitant with strong CYP3A4 inhibitors should be approached cautiously. - When a single 375-mg dose of Aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of Aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of Aprepitant. - Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of Aprepitant with digoxin in a clinical drug interaction study. - Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone. - Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0‑24hr of 31.3 mcghr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0‑24hr of 26.9 mcghr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aprepitant in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Aprepitant during labor and delivery. ### Nursing Mothers - Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness of Aprepitant in pediatric patients have not been established. ### Geriatic Use - In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with Aprepitant 31% were 65 and over, while 5% were 75 and over. In well-controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with Aprepitant 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. ### Gender There is no FDA guidance on the use of Aprepitant with respect to specific gender populations. ### Race There is no FDA guidance on the use of Aprepitant with respect to specific racial populations. ### Renal Impairment - No dosage adjustment is necessary for patients with renal impairment or for patients with ]]end stage renal disease]] (ESRD) undergoing hemodialysis. ### Hepatic Impairment - No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic impairment (Child-Pugh score >9). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Aprepitant in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Aprepitant in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Aprepitant Administration in the drug label. ### Monitoring There is limited information regarding Aprepitant Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Aprepitant and IV administrations. # Overdosage No specific information is available on the treatment of overdosage. Drowsiness and headache were reported in one patient who ingested 1440 mg of aprepitant. In the event of overdose, Aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. # Pharmacology ## Mechanism of Action - Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). - Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis. ## Structure - Chemically described as 5-(2R,3S)-2-ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one. - Its empirical formula is C23H21F7N4O3, and its structural formula is: ## Pharmacodynamics - In two single-blind, multiple-dose, randomized, and placebo control studies, healthy young men received oral aprepitant doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant concentration and NK1 receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of ~10 ng/mL and ~100 ng/mL, the NK1 receptor occupancies were ~50% and ~90%, respectively. The oral aprepitant regimen for CINV produces mean trough plasma aprepitant concentrations >500 ng/mL, which would be expected to, based on the fitted curve with the Hill equation, result in >95% brain NK1 receptor occupancy. However, the receptor occupancy for either CINV or PONV dosing regimen has not been determined. In addition, the relationship between NK1 receptor occupancy and the clinical efficacy of aprepitant has not been established. - In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant had no effect on the QTc interval. QT prolongation with the oral dosing regimens for CINV and PONV are not expected. ## Pharmacokinetics - Following oral administration of a single 40 mg dose of Aprepitant in the fasted state, mean area under the plasma concentration-time curve (AUC0‑∞) was 7.8 mcghr/mL and mean peak plasma concentration (Cmax) was 0.7 mcg/mL, occurring at approximately 3 hours postdose (Tmax). The absolute bioavailability at the 40‑mg dose has not been determined. - Following oral administration of a single 125-mg dose of Aprepitant on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24hr was approximately 19.6 mcghr/mL and 21.2 mcghr/mL on Day 1 and Day 3, respectively. The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively. At the dose range of 80-125 mg, the mean absolute oral bioavailability of aprepitant is approximately 60 to 65%. Oral administration of the capsule with a standard high-fat breakfast had no clinically meaningful effect on the bioavailability of aprepitant. - The pharmacokinetics of aprepitant are non-linear across the clinical dose range. In healthy young adults, the increase in AUC0‑∞ was 26% greater than dose proportional between 80‑mg and 125‑mg single doses administered in the fed state. - Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) is approximately 70 L in humans. Aprepitant crosses the placenta in rats and rabbits and crosses the blood brain barrier in humans. - Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of -aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. - Following administration of a single IV 100-mg dose of -aprepitant prodrug to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces. A study was not conducted with radiolabeled capsule formulation. The results after oral administration may differ. - Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent plasma clearance of aprepitant ranged from approximately 62 to 90 mL/min. The apparent terminal half-life ranged from approximately 9 to 13 hours. ## Nonclinical Toxicology - Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0‑24hr) of 0.7 to 1.6 times the human exposure (AUC0‑24hr = 19.6 mcghr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and thyroid carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. - Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test. - Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). # Clinical Studies ### Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) - Oral administration of Aprepitant in combination with ondansetron and dexamethasone (aprepitant regimen) has been shown to prevent acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy including high-dose cisplatin, and nausea and vomiting associated with moderately emetogenic chemotherapy. - In 2 multicenter, randomized, parallel, double-blind, controlled clinical studies, the aprepitant regimen (see Table 6) was compared with standard therapy in patients receiving a chemotherapy regimen that included cisplatin >50 mg/m2 (mean cisplatin dose = 80.2 mg/m2). Of the 550 patients who were randomized to receive the aprepitant regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The aprepitant-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. 170 patients were 65 years or older, with 29 patients being 75 years or older. Patients (N = 1105) were randomized to either the aprepitant regimen (N = 550) or standard therapy (N = 555). The treatment regimens are defined in Table 5. - During these studies 95% of the patients in the aprepitant group received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of aprepitant patients exposed follows: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11). - The antiemetic activity of Aprepitant was evaluated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours post-cisplatin treatment) in Cycle 1. Efficacy was based on evaluation of the following endpoints: - Complete response (defined as no emetic episodes and no use of rescue therapy) - Complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale ]] score <25 mm on a 0 to 100 mm scale) - No emesis (defined as no emetic episodes regardless of use of rescue therapy) - No nausea (maximum VAS <5 mm on a 0 to 100 mm scale) - No significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale) - In both studies, a statistically significantly higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately. - In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the aprepitant regimen, and the incidence of first emesis was reduced in the aprepitant regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1. - Patient-Reported Outcomes: The impact of nausea and vomiting on patients’ daily lives was assessed in Cycle 1 of both Phase III studies using the Functional Living Index–Emesis (FLIE), a validated nausea- and vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients’ daily lives is defined as a FLIE total score >108. In each of the 2 studies, a higher proportion of patients receiving the aprepitant regimen reported minimal or no impact of nausea and vomiting on daily life (Study 1: 74% versus 64%; Study 2: 75% versus 64%). - Multiple-Cycle Extension: In the same 2 clinical studies, patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The proportion of patients with no emesis and no significant nausea by treatment group at each cycle is depicted in Figure 2. Antiemetic effectiveness for the patients receiving the aprepitant regimen is maintained throughout repeat - In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, the aprepitant regimen (see Table 9) was compared with a standard of care therapy in patients receiving a moderately emetogenic chemotherapy regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin (≤60 mg/m2) or epirubicin (≤100 mg/m2). In this study, the most common combinations were cyclophosphamide + doxorubicin (60.6%); and cyclophosphamide + epirubicin + fluorouracil (21.6%). Of the 438 patients who were randomized to receive the aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and <1% Other. The aprepitant-treated patients in this clinical study ranged from 25 to 78 years of age, with a mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years. Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). The treatment regimens are defined in Table 8. - Primary endpoint: Complete response (defined as no emetic episodes and no use of rescue therapy) in the overall phase (0 to 120 hours post-chemotherapy) - Complete response (defined as no emetic episodes and no use of rescue therapy) in the overall phase (0 to 120 hours post-chemotherapy) - No emesis (defined as no emetic episodes regardless of use of rescue therapy) - No nausea (maximum VAS <5 mm on a 0 to 100 mm scale) - No significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale) - Complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale score <25 mm on a 0 to 100 mm scale) complete response during the acute and delayed phases. A summary of the key results from this study is shown in Table 9. - In this study, a statistically significantly (p=0.015) higher proportion of patients receiving the aprepitant regimen (51%) in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy (42%). The difference between treatment groups was primarily driven by the “No Emesis Endpoint”, a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response during the acute (0-24 hours) and delayed (25-120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments. - Patient-Reported Outcomes: In a phase III study in patients receiving moderately emetogenic chemotherapy, the impact of nausea and vomiting on patients’ daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the aprepitant regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the “No Vomiting Domain” of this composite endpoint. - Multiple-Cycle Extension: Patients receiving moderately emetogenic chemotherapy were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. Antiemetic effect for patients receiving the aprepitant regimen is maintained during all cycles. - Postmarketing Trial: In a postmarketing, multicenter, randomized, double-blind, parallel-group, clinical study in 848 cancer patients, the aprepitant regimen (N = 430) was compared with a standard of care therapy (N = 418) in patients receiving a moderately emetogenic chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV (1 g/m2). - Of the 430 patients who were randomized to receive the aprepitant regimen, approximately 76% were women and 24% were men. The distribution by race was 67% White, 6% Black or African American, 11% Asian, and 12% multiracial. Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic. The aprepitant-treated patients in this clinical study ranged from 22 to 85 years of age, with a mean age of 57 years; approximately 59% of the patients were 55 years or older with 32 patients being over 74 years. Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumor types including 50% with breast cancer, 21% with gastrointestinal cancers including colorectal cancer, 13% with lung cancer and 6% with gynecological cancers. - The antiemetic activity of Aprepitant was evaluated based on no vomiting (with or without rescue therapy) in the overall period (0 to 120 hours post-chemotherapy) and complete response (defined as no vomiting and no use of rescue therapy) in the overall period. A summary of the key results from this study is shown in Table 10. - In this study, a statistically significantly higher proportion of patients receiving the aprepitant regimen (76%) in Cycle 1 had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, a higher proportion of patients receiving the aprepitant regimen (69%) in Cycle 1 had a complete response in the overall phase (0-120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively). - In a subgroup analysis by tumor type, a numerically higher proportion of patients receiving aprepitant were observed to have no vomiting and complete response compared to patients receiving standard therapy. For gender, the difference in complete response rates between the aprepitant and standard regimen groups was 14% in females (64.5% and 50.3%, respectively) and 4% in males (82.2% and 78.2%, respectively) during the overall phase. A similar difference for gender was observed for the no vomiting endpoint. ### Prevention of Postoperative Nausea and Vomiting (PONV) - In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (PONV Studies 1 and 2), aprepitant was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. Patients were randomized to receive 40 mg aprepitant, 125 mg aprepitant, or 4 mg ondansetron. Aprepitant was given orally with 50 mL of water 1 to 3 hours before anesthesia. Ondansetron was given intravenously immediately before induction of anesthesia. A comparison between the 125 mg dose and the 40 mg dose did not demonstrate any additional clinical benefit. The remainder of this section will focus on the results in the 40 mg aprepitant dose recommended for PONV. - Of the 564 patients who received 40 mg aprepitant, 92% were women and 8% were men; of these, 58% were White, 13% Hispanic American, 7% Multi-Racial, 14% Black, 6% Asian, and 2% Other. The age of patients treated with 40 mg aprepitant ranged from 19 to 84 years, with a mean age of 46.1 years. 46 patients were 65 years or older, with 13 patients being 75 years or older. The antiemetic activity of Aprepitant was evaluated during the 0 to 48 hour period following the end of surgery. The two pivotal studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. PONV Study 1 was a multinational study including the U.S., whereas, PONV Study 2 was conducted entirely in the U.S. - No emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) - Complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) - No emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary) - Time to first use of rescue medication in the 0 to 24 hours following the end of surgery (exploratory) - Time to first emesis in the 0 to 48 hours following the end of surgery (exploratory). A closed testing procedure was applied to control the type I error for the primary endpoints. The results of the primary and secondary endpoints for 40 mg aprepitant and 4 mg ondansetron are described in Table 11: - The use of aprepitant did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of aprepitant delayed the time to first vomiting, as depicted in Figure 3. - Efficacy measures in PONV Study 2 included: complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (secondary) no use of rescue therapy in the 0 to 24 hours following the end of surgery (secondary) no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary). PONV Study 2 failed to satisfy its primary hypothesis that aprepitant is superior to ondansetron in the prevention of PONV as measured by the proportion of patients with complete response in the 24 hours following end of surgery. - complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) - no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (secondary) - no use of rescue therapy in the 0 to 24 hours following the end of surgery (secondary) - no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary). - PONV Study 2 failed to satisfy its primary hypothesis that aprepitant is superior to ondansetron in the prevention of PONV as measured by the proportion of patients with complete response in the 24 hours following end of surgery. The study demonstrated that both dose levels of aprepitant had a clinically meaningful effect with respect to the secondary endpoint “no vomiting” during the first 24 hours after surgery and showed that the use of 40 mg aprepitant was associated with a 16% improvement over ondansetron for the no vomiting endpoint. # How Supplied No. 3854 — 80 mg capsules: White, opaque, hard gelatin capsule with “461” and “80 mg” printed radially in black ink on the body. They are supplied as follows: - NDC 54868-5231-2 unit-of-use BiPack of 2 - NDC 54868-5231-3 unit-of-use BiPack of 4 - NDC 54868-5231-1 unit-dose package of 6. ## Storage Store at 20-25°C (68-77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Aprepitant Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Aprepitant (patient information) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Emend # Look-Alike Drug Names There is limited information regarding Aprepitant Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Aprepitant Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Aprepitant is an antiemetic, neurokinin-1 receptor antagonist that is FDA approved for the prophylaxis of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin and nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). Its also, indicated for the prevention of postoperative nausea and vomiting (PONV). Common adverse reactions include alopecia, anorexia, asthenia/fatigue, constipation, diarrhea, headache, hiccups, nausea, hypotension, pruritus, pyrexia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Capsules of Aprepitant (aprepitant) are given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of Aprepitant is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3. - Aprepitant may be taken with or without food. - Aprepitant (fosaprepitant dimeglumine) for Injection (115 mg) is a prodrug of aprepitant and may be substituted for oral Aprepitant (125 mg), 30 minutes prior to chemotherapy, on Day 1 only of the CINV regimen as an intravenous infusion administered over 15 minutes. In clinical studies with Aprepitant, the following regimen was used for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy: In a clinical study with Aprepitant, the following regimen was used for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy: - The recommended oral dosage of Aprepitant is 40 mg within 3 hours prior to induction of anesthesia. Aprepitant may be taken with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Aprepitant (patient information) in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Aprepitant (patient information) in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Aprepitant FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Aprepitant (patient information) in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Aprepitant (patient information) in pediatric patients. # Contraindications - Aprepitant is contraindicated in patients who are hypersensitive to any component of the product. Aprepitant is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). Aprepitant should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. # Warnings - Aprepitant (aprepitant), a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125 mg/80 mg regimen, could result in elevated plasma concentrations of these concomitant medications. - Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. - When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When Aprepitant is used concomitantly with medications that induce CYP3A4 activity aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of Aprepitant. - Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, Aprepitant (125 mg/80 mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. - In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when Aprepitant (125 mg/80 mg regimen) was co-administered. - Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. - Coadministration of Aprepitant with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of Aprepitant with each chemotherapy cycle, or following administration of a single 40 mg dose of Aprepitant for the prevention of postoperative nausea and vomiting. - Upon coadministration with Aprepitant, the efficacy of hormonal contraceptives during and for 28 days following the last dose of Aprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with Aprepitant and for 1 month following the last dose of Aprepitant. - There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when Aprepitant is administered in these patients. - Chronic continuous use of Aprepitant for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use. # Adverse Reactions ## Clinical Trials Experience - In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. Aprepitant was given in combination with ondansetron and dexamethasone. - In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Table 1 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3%. - In a combined analysis of these two studies, isolated cases of serious adverse experiences were similar in the two treatment groups. ### Highly and Moderately Emetogenic Chemotherapy The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen in either HEC or MEC studies: - Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection. - Neoplasms benign, malignant and unspecified (including cysts and polyps): malignant neoplasm, non-small cell lung carcinoma. - Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia. - Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia. - Psychiatric disorders: anxiety disorder, confusion, depression. - Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor. - Eye disorders: conjunctivitis. - Cardiac disorders: myocardial infarction, palpitations, tachycardia. - Vascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotension. - Respiratory, thoracic and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance. - Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased. - Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash. - Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia. - Renal and urinary disorders: dysuria, renal insufficiency. - Reproductive system and breast disorders: pelvic pain. - General disorders and administrative site conditions: edema, malaise, pain, rigors. - Investigations: weight loss. - Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study. ### Laboratory Adverse Experiences Table 3 shows the percent of patients with laboratory adverse experiences reported at an incidence ≥3% in patients receiving highly emetogenic chemotherapy - The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia. The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1. - In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron IV. - Clinical adverse experiences were reported in approximately 60% of patients treated with 40 mg aprepitant compared with approximately 64% of patients treated with 4 mg ondansetron IV. Table 4 shows the percent of patients with clinical adverse experiences reported at an incidence ≥3% of the combined studies. The following additional clinical adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant: - Infections and infestations: postoperative infection - Metabolism and nutrition disorders: hypokalemia, hypovolemia. - Nervous system disorders: dizziness, hypoesthesia, syncope. - Vascular disorders: hematoma - Respiratory, thoracic and mediastinal disorders: dyspnea, hypoxia, respiratory depression. - Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia. - Skin and subcutaneous tissue disorders: urticaria - General disorders and administrative site conditions: hypothermia, pain. - Investigations: hypotension - Injury, poisoning and procedural complications: operative hemorrhage, wound dehiscence. Other adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included: - Nervous system disorders: dysarthria, sensory disturbance. - Eye disorders: miosis, visual acuity reduced. - Respiratory, thoracic and mediastinal disorders: wheezing - Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort. There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40 mg aprepitant. ### Laboratory Adverse Experiences - One laboratory adverse experience, hemoglobin decreased (40 mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia. - The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present. The adverse experience of ALT increased occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%). ### Other Studies - In addition, two serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of sub-ileus. - Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study. ## Postmarketing Experience The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug. - Skin and subcutaneous tissue disorders: pruritus, rash, urticaria. - Immune system disorders: hypersensitivity reactions including anaphylactic reactions. # Drug Interactions - Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect. - As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg). - In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). - Dexamethasone: Aprepitant, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and Aprepitant when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with Aprepitant (125 mg/80 mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without Aprepitant. The daily dose of dexamethasone administered in clinical chemotherapy induced nausea and vomiting studies with Aprepitant reflects an approximate 50% reduction of the dose of dexamethasone. A single dose of Aprepitant (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended. - Methylprednisolone: Aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with Aprepitant (125 mg/80 mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without Aprepitant Although the concomitant administration of methylprednisolone with the single 40 mg dose of aprepitant has not been studied, a single 40 mg dose of Aprepitant produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended. - Docetaxel: In a pharmacokinetic study, Aprepitant (125 mg/80 mg regimen) did not influence the pharmacokinetics of docetaxel. - Vinorelbine: In a pharmacokinetic study, Aprepitant (125 mg/80 mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree. - Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of Aprepitant with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs. - A single 125-mg dose of Aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of Aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with Aprepitant In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of Aprepitant with each chemotherapy cycle, or following administration of a single 40 mg dose of Aprepitant for the prevention of postoperative nausea and vomiting. - Aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of Aprepitant and on Days 4, 8, and 15. - Aprepitant, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of Aprepitant 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important. - Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%. - In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and Aprepitant was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of Aprepitant on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21. - In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and Aprepitant 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with Aprepitant 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone. - The coadministration of Aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of Aprepitant. Alternative or back-up methods of contraception should be used during treatment with Aprepitant and for 1 month following the last dose of Aprepitant. - Aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of Aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with Aprepitant (125 mg/80 mg). A single dose of Aprepitant (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with Aprepitant 40 mg; this effect was not considered clinically important. - In another study with intravenous administration of midazolam, Aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of Aprepitant and on Days 4, 8, and 15. Aprepitant increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of Aprepitant on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline. - An additional study was completed with intravenous administration of midazolam and Aprepitant. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of Aprepitant 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (e.g., elderly patients) and degree of monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with Aprepitant for the chemotherapy induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3). - Aprepitant is a substrate for CYP3A4; therefore, coadministration of Aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of Aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. - Aprepitant is a substrate for CYP3A4; therefore, coadministration of Aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of Aprepitant. - When a single 125-mg dose of Aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of Aprepitant with strong CYP3A4 inhibitors should be approached cautiously. - When a single 375-mg dose of Aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of Aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of Aprepitant. - Aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of Aprepitant with digoxin in a clinical drug interaction study. - Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone. - Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0‑24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0‑24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aprepitant in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Aprepitant during labor and delivery. ### Nursing Mothers - Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness of Aprepitant in pediatric patients have not been established. ### Geriatic Use - In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with Aprepitant 31% were 65 and over, while 5% were 75 and over. In well-controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with Aprepitant 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. ### Gender There is no FDA guidance on the use of Aprepitant with respect to specific gender populations. ### Race There is no FDA guidance on the use of Aprepitant with respect to specific racial populations. ### Renal Impairment - No dosage adjustment is necessary for patients with renal impairment or for patients with ]]end stage renal disease]] (ESRD) undergoing hemodialysis. ### Hepatic Impairment - No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic impairment (Child-Pugh score >9). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Aprepitant in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Aprepitant in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Aprepitant Administration in the drug label. ### Monitoring There is limited information regarding Aprepitant Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Aprepitant and IV administrations. # Overdosage No specific information is available on the treatment of overdosage. Drowsiness and headache were reported in one patient who ingested 1440 mg of aprepitant. In the event of overdose, Aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. # Pharmacology ## Mechanism of Action - Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). - Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis. ## Structure - Chemically described as 5-(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one. - Its empirical formula is C23H21F7N4O3, and its structural formula is: ## Pharmacodynamics - In two single-blind, multiple-dose, randomized, and placebo control studies, healthy young men received oral aprepitant doses of 10 mg (N=2), 30 mg (N=3), 100 mg (N=3) or 300 mg (N=5) once daily for 14 days with 2 or 3 subjects on placebo. Both plasma aprepitant concentration and NK1 receptor occupancy in the corpus striatum by positron emission tomography were evaluated, at predose and 24 hours after the last dose. At aprepitant plasma concentrations of ~10 ng/mL and ~100 ng/mL, the NK1 receptor occupancies were ~50% and ~90%, respectively. The oral aprepitant regimen for CINV produces mean trough plasma aprepitant concentrations >500 ng/mL, which would be expected to, based on the fitted curve with the Hill equation, result in >95% brain NK1 receptor occupancy. However, the receptor occupancy for either CINV or PONV dosing regimen has not been determined. In addition, the relationship between NK1 receptor occupancy and the clinical efficacy of aprepitant has not been established. - In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant had no effect on the QTc interval. QT prolongation with the oral dosing regimens for CINV and PONV are not expected. ## Pharmacokinetics - Following oral administration of a single 40 mg dose of Aprepitant in the fasted state, mean area under the plasma concentration-time curve (AUC0‑∞) was 7.8 mcg•hr/mL and mean peak plasma concentration (Cmax) was 0.7 mcg/mL, occurring at approximately 3 hours postdose (Tmax). The absolute bioavailability at the 40‑mg dose has not been determined. - Following oral administration of a single 125-mg dose of Aprepitant on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24hr was approximately 19.6 mcg•hr/mL and 21.2 mcg•hr/mL on Day 1 and Day 3, respectively. The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively. At the dose range of 80-125 mg, the mean absolute oral bioavailability of aprepitant is approximately 60 to 65%. Oral administration of the capsule with a standard high-fat breakfast had no clinically meaningful effect on the bioavailability of aprepitant. - The pharmacokinetics of aprepitant are non-linear across the clinical dose range. In healthy young adults, the increase in AUC0‑∞ was 26% greater than dose proportional between 80‑mg and 125‑mg single doses administered in the fed state. - Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) is approximately 70 L in humans. Aprepitant crosses the placenta in rats and rabbits and crosses the blood brain barrier in humans. - Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. - Following administration of a single IV 100-mg dose of [14C]-aprepitant prodrug to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces. A study was not conducted with radiolabeled capsule formulation. The results after oral administration may differ. - Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent plasma clearance of aprepitant ranged from approximately 62 to 90 mL/min. The apparent terminal half-life ranged from approximately 9 to 13 hours. ## Nonclinical Toxicology - Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0‑24hr) of 0.7 to 1.6 times the human exposure (AUC0‑24hr = 19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and thyroid carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. - Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test. - Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). # Clinical Studies ### Prevention of Chemotherapy Induced Nausea and Vomiting (CINV) - Oral administration of Aprepitant in combination with ondansetron and dexamethasone (aprepitant regimen) has been shown to prevent acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy including high-dose cisplatin, and nausea and vomiting associated with moderately emetogenic chemotherapy. - In 2 multicenter, randomized, parallel, double-blind, controlled clinical studies, the aprepitant regimen (see Table 6) was compared with standard therapy in patients receiving a chemotherapy regimen that included cisplatin >50 mg/m2 (mean cisplatin dose = 80.2 mg/m2). Of the 550 patients who were randomized to receive the aprepitant regimen, 42% were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and 21% Multi-Racial. The aprepitant-treated patients in these clinical studies ranged from 14 to 84 years of age, with a mean age of 56 years. 170 patients were 65 years or older, with 29 patients being 75 years or older. Patients (N = 1105) were randomized to either the aprepitant regimen (N = 550) or standard therapy (N = 555). The treatment regimens are defined in Table 5. - During these studies 95% of the patients in the aprepitant group received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common chemotherapeutic agents and the number of aprepitant patients exposed follows: etoposide (106), fluorouracil (100), gemcitabine (89), vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38), docetaxel (11). - The antiemetic activity of Aprepitant was evaluated during the acute phase (0 to 24 hours post-cisplatin treatment), the delayed phase (25 to 120 hours post-cisplatin treatment) and overall (0 to 120 hours post-cisplatin treatment) in Cycle 1. Efficacy was based on evaluation of the following endpoints: - Complete response (defined as no emetic episodes and no use of rescue therapy) - Complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [[[VAS]]] score <25 mm on a 0 to 100 mm scale) - No emesis (defined as no emetic episodes regardless of use of rescue therapy) - No nausea (maximum VAS <5 mm on a 0 to 100 mm scale) - No significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale) - In both studies, a statistically significantly higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response in the overall phase (primary endpoint), compared with patients receiving standard therapy. A statistically significant difference in complete response in favor of the aprepitant regimen was also observed when the acute phase and the delayed phase were analyzed separately. - In both studies, the estimated time to first emesis after initiation of cisplatin treatment was longer with the aprepitant regimen, and the incidence of first emesis was reduced in the aprepitant regimen group compared with standard therapy group as depicted in the Kaplan-Meier curves in Figure 1. - Patient-Reported Outcomes: The impact of nausea and vomiting on patients’ daily lives was assessed in Cycle 1 of both Phase III studies using the Functional Living Index–Emesis (FLIE), a validated nausea- and vomiting-specific patient-reported outcome measure. Minimal or no impact of nausea and vomiting on patients’ daily lives is defined as a FLIE total score >108. In each of the 2 studies, a higher proportion of patients receiving the aprepitant regimen reported minimal or no impact of nausea and vomiting on daily life (Study 1: 74% versus 64%; Study 2: 75% versus 64%). - Multiple-Cycle Extension: In the same 2 clinical studies, patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The proportion of patients with no emesis and no significant nausea by treatment group at each cycle is depicted in Figure 2. Antiemetic effectiveness for the patients receiving the aprepitant regimen is maintained throughout repeat - In a multicenter, randomized, double-blind, parallel-group, clinical study in breast cancer patients, the aprepitant regimen (see Table 9) was compared with a standard of care therapy in patients receiving a moderately emetogenic chemotherapy regimen that included cyclophosphamide 750-1500 mg/m2; or cyclophosphamide 500-1500 mg/m2 and doxorubicin (≤60 mg/m2) or epirubicin (≤100 mg/m2). In this study, the most common combinations were cyclophosphamide + doxorubicin (60.6%); and cyclophosphamide + epirubicin + fluorouracil (21.6%). Of the 438 patients who were randomized to receive the aprepitant regimen, 99.5% were women. Of these, approximately 80% were White, 8% Black, 8% Asian, 4% Hispanic, and <1% Other. The aprepitant-treated patients in this clinical study ranged from 25 to 78 years of age, with a mean age of 53 years; 70 patients were 65 years or older, with 12 patients being over 74 years. Patients (N = 866) were randomized to either the aprepitant regimen (N = 438) or standard therapy (N = 428). The treatment regimens are defined in Table 8. - Primary endpoint: Complete response (defined as no emetic episodes and no use of rescue therapy) in the overall phase (0 to 120 hours post-chemotherapy) - Complete response (defined as no emetic episodes and no use of rescue therapy) in the overall phase (0 to 120 hours post-chemotherapy) - No emesis (defined as no emetic episodes regardless of use of rescue therapy) - No nausea (maximum VAS <5 mm on a 0 to 100 mm scale) - No significant nausea (maximum VAS <25 mm on a 0 to 100 mm scale) - Complete protection (defined as no emetic episodes, no use of rescue therapy, and a maximum nausea visual analogue scale [VAS] score <25 mm on a 0 to 100 mm scale) complete response during the acute and delayed phases. A summary of the key results from this study is shown in Table 9. - In this study, a statistically significantly (p=0.015) higher proportion of patients receiving the aprepitant regimen (51%) in Cycle 1 had a complete response (primary endpoint) during the overall phase compared with patients receiving standard therapy (42%). The difference between treatment groups was primarily driven by the “No Emesis Endpoint”, a principal component of this composite primary endpoint. In addition, a higher proportion of patients receiving the aprepitant regimen in Cycle 1 had a complete response during the acute (0-24 hours) and delayed (25-120 hours) phases compared with patients receiving standard therapy; however, the treatment group differences failed to reach statistical significance, after multiplicity adjustments. - Patient-Reported Outcomes: In a phase III study in patients receiving moderately emetogenic chemotherapy, the impact of nausea and vomiting on patients’ daily lives was assessed in Cycle 1 using the FLIE. A higher proportion of patients receiving the aprepitant regimen reported minimal or no impact on daily life (64% versus 56%). This difference between treatment groups was primarily driven by the “No Vomiting Domain” of this composite endpoint. - Multiple-Cycle Extension: Patients receiving moderately emetogenic chemotherapy were permitted to continue into the Multiple-Cycle extension of the study for up to 3 additional cycles of chemotherapy. Antiemetic effect for patients receiving the aprepitant regimen is maintained during all cycles. - Postmarketing Trial: In a postmarketing, multicenter, randomized, double-blind, parallel-group, clinical study in 848 cancer patients, the aprepitant regimen (N = 430) was compared with a standard of care therapy (N = 418) in patients receiving a moderately emetogenic chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV (<1500 mg/m2); or cytarabine IV (>1 g/m2). - Of the 430 patients who were randomized to receive the aprepitant regimen, approximately 76% were women and 24% were men. The distribution by race was 67% White, 6% Black or African American, 11% Asian, and 12% multiracial. Classified by ethnicity, 36% were Hispanic and 64% were non-Hispanic. The aprepitant-treated patients in this clinical study ranged from 22 to 85 years of age, with a mean age of 57 years; approximately 59% of the patients were 55 years or older with 32 patients being over 74 years. Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumor types including 50% with breast cancer, 21% with gastrointestinal cancers including colorectal cancer, 13% with lung cancer and 6% with gynecological cancers. - The antiemetic activity of Aprepitant was evaluated based on no vomiting (with or without rescue therapy) in the overall period (0 to 120 hours post-chemotherapy) and complete response (defined as no vomiting and no use of rescue therapy) in the overall period. A summary of the key results from this study is shown in Table 10. - In this study, a statistically significantly higher proportion of patients receiving the aprepitant regimen (76%) in Cycle 1 had no vomiting during the overall phase compared with patients receiving standard therapy (62%). In addition, a higher proportion of patients receiving the aprepitant regimen (69%) in Cycle 1 had a complete response in the overall phase (0-120 hours) compared with patients receiving standard therapy (56%). In the acute phase (0 to 24 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (92% and 84%, respectively) and complete response (89% and 80%, respectively). In the delayed phase (25 to 120 hours following initiation of chemotherapy), a higher proportion of patients receiving aprepitant compared to patients receiving standard therapy were observed to have no vomiting (78% and 67%, respectively) and complete response (71% and 61%, respectively). - In a subgroup analysis by tumor type, a numerically higher proportion of patients receiving aprepitant were observed to have no vomiting and complete response compared to patients receiving standard therapy. For gender, the difference in complete response rates between the aprepitant and standard regimen groups was 14% in females (64.5% and 50.3%, respectively) and 4% in males (82.2% and 78.2%, respectively) during the overall phase. A similar difference for gender was observed for the no vomiting endpoint. ### Prevention of Postoperative Nausea and Vomiting (PONV) - In two multicenter, randomized, double-blind, active comparator-controlled, parallel-group clinical studies (PONV Studies 1 and 2), aprepitant was compared with ondansetron for the prevention of postoperative nausea and vomiting in 1658 patients undergoing open abdominal surgery. Patients were randomized to receive 40 mg aprepitant, 125 mg aprepitant, or 4 mg ondansetron. Aprepitant was given orally with 50 mL of water 1 to 3 hours before anesthesia. Ondansetron was given intravenously immediately before induction of anesthesia. A comparison between the 125 mg dose and the 40 mg dose did not demonstrate any additional clinical benefit. The remainder of this section will focus on the results in the 40 mg aprepitant dose recommended for PONV. - Of the 564 patients who received 40 mg aprepitant, 92% were women and 8% were men; of these, 58% were White, 13% Hispanic American, 7% Multi-Racial, 14% Black, 6% Asian, and 2% Other. The age of patients treated with 40 mg aprepitant ranged from 19 to 84 years, with a mean age of 46.1 years. 46 patients were 65 years or older, with 13 patients being 75 years or older. The antiemetic activity of Aprepitant was evaluated during the 0 to 48 hour period following the end of surgery. The two pivotal studies were of similar design; however, they differed in terms of study hypothesis, efficacy analyses and geographic location. PONV Study 1 was a multinational study including the U.S., whereas, PONV Study 2 was conducted entirely in the U.S. - No emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) - Complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) - No emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary) - Time to first use of rescue medication in the 0 to 24 hours following the end of surgery (exploratory) - Time to first emesis in the 0 to 48 hours following the end of surgery (exploratory). A closed testing procedure was applied to control the type I error for the primary endpoints. The results of the primary and secondary endpoints for 40 mg aprepitant and 4 mg ondansetron are described in Table 11: - The use of aprepitant did not affect the time to first use of rescue medication when compared to ondansetron. However, compared to the ondansetron group, use of aprepitant delayed the time to first vomiting, as depicted in Figure 3. - Efficacy measures in PONV Study 2 included: complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (secondary) no use of rescue therapy in the 0 to 24 hours following the end of surgery (secondary) no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary). PONV Study 2 failed to satisfy its primary hypothesis that aprepitant is superior to ondansetron in the prevention of PONV as measured by the proportion of patients with complete response in the 24 hours following end of surgery. - complete response (defined as no emetic episodes and no use of rescue therapy) in the 0 to 24 hours following the end of surgery (primary) - no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 24 hours following the end of surgery (secondary) - no use of rescue therapy in the 0 to 24 hours following the end of surgery (secondary) - no emesis (defined as no emetic episodes regardless of use of rescue therapy) in the 0 to 48 hours following the end of surgery (secondary). - PONV Study 2 failed to satisfy its primary hypothesis that aprepitant is superior to ondansetron in the prevention of PONV as measured by the proportion of patients with complete response in the 24 hours following end of surgery. The study demonstrated that both dose levels of aprepitant had a clinically meaningful effect with respect to the secondary endpoint “no vomiting” during the first 24 hours after surgery and showed that the use of 40 mg aprepitant was associated with a 16% improvement over ondansetron for the no vomiting endpoint. # How Supplied No. 3854 — 80 mg capsules: White, opaque, hard gelatin capsule with “461” and “80 mg” printed radially in black ink on the body. They are supplied as follows: - NDC 54868-5231-2 unit-of-use BiPack of 2 - NDC 54868-5231-3 unit-of-use BiPack of 4 - NDC 54868-5231-1 unit-dose package of 6. ## Storage Store at 20-25°C (68-77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Aprepitant Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Aprepitant (patient information) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Emend # Look-Alike Drug Names There is limited information regarding Aprepitant Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Aprepitant
94b9a8f6569ee2644c9fc3074e6fc564e161b44b	wikidoc	Aprosodias	Aprosodias # Overview Aprosodias are defined as acquired or developmental conditions marked by an imparied ability to comprehend or generate the emotion conveyed in spoken language. # Symptoms Aprosodias have several subtypes: - Motor aprosodia - Sensory aprosodia - Global aprosodia - Transcortical motor aprosodia - Transcortical sensory aprosodia - Mixed transcortical aprosodia - Expressive aprosodia – Disruption in pitch, loudness, rate, or rhythm that convey a speaker’s emotional intent. It can have devastating effects on communication and personal relationship. It is less awareness than for aphasia. Partner or family may think they have become “uncaring” # Proposed Mechanisms Aprosoidas are caused by impairment of non-dominant hemisphere, manifested with inability of affective expression and comprehension. Its anatomical location homologous to aphasic syndrome due to dominant hemisphere damage. # Related Chapters - Aphasia - Apraxia - Communication disorder de:Aprosodie	Aprosodias Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Aprosodias are defined as acquired or developmental conditions marked by an imparied ability to comprehend or generate the emotion conveyed in spoken language. # Symptoms Aprosodias have several subtypes: - Motor aprosodia - Sensory aprosodia - Global aprosodia - Transcortical motor aprosodia - Transcortical sensory aprosodia - Mixed transcortical aprosodia - Expressive aprosodia – Disruption in pitch, loudness, rate, or rhythm that convey a speaker’s emotional intent. It can have devastating effects on communication and personal relationship. It is less awareness than for aphasia. Partner or family may think they have become “uncaring” # Proposed Mechanisms Aprosoidas are caused by impairment of non-dominant hemisphere, manifested with inability of affective expression and comprehension. Its anatomical location homologous to aphasic syndrome due to dominant hemisphere damage. # Related Chapters - Aphasia - Apraxia - Communication disorder de:Aprosodie	https://www.wikidoc.org/index.php/Aprosodias
ee92df5d8a7f144b16839df942d779287af61862	wikidoc	Aqua Detox	Aqua Detox Aqua Detox is a device promoted for use in detoxification, based on the research of Royal Rife and involves soaking an individual's feet in a saline bath through which an electrical current is passed. The device has been criticized for misleading consumers. The device, or something similar, is marketed under a wide variety of names. due to the company responsible for developing the original device offers offers in-house web-design services for resellers. As of October 15th, 2006, the Aqua Detox brand officially came under a new umbrella company called The Agenta Group. # Manufacturer claims According to its manufacturer, the Aqua Detox system produces positive and negative ions, that "resonate through the body and stimulates the cells within it", claiming that this 'rebalances' cellular energy, allowing efficient performance and excretion of toxins that have accumulated within the tissues and that 20 - 35 minutes of usage every second or third day causes toxins from throughout the body to be excreted from the 2000 pores of the feet The manufacturer currently lacks evidence to demonstrate any detoxifying effect, but claims it is conducting a clinical trial to establish proof.. # Criticisms Although the manufacturer does not make direct claims for Aqua Detox in the treatment or cure of disease, the Aqua Detox International was the subject of a British Advertising Standards Authority adjudication for April 6, 2005, specifically challenging the use of user testimonials which implied efficacy in serious disease, and challenges to the general efficacy of the device; both complaints were upheld, with the advertiser not addressing the efficacy of the device but promising to remove the misleading testimonials from their advertisements. The marketer Miracle Beauty claims that the color of the bath indicates what areas have allegedly been cleansed of toxins: black for liver, orange for joints, green for gall bladder. Aqua detox machines have iron electrodes that corrode to generate rust and tint the water brown when used to electrolyze saline in the footbath. The different variations in color can be accounted by varying amount of salt added to the water and variations in the compositions of the electrodes. An experiment with salt water and a car battery showed that the water will change color regardless, whether there are feet in the water or not, and that the composition the analyzed water was the same in both cases. Barrett claims that it's nothing more than electrolysis, or rusting of the electrodes in the case of iron, and the change in color is being used by the manufacturers to mislead the consumers. Aqua Detox has not been evaluated by the US Food and Drug Administration, and marketing materials related to the product carry a disclaimer to the effect that "it is not intended to diagnose, treat, cure, or prevent any disease."	Aqua Detox Aqua Detox is a device promoted for use in detoxification, based on the research of Royal Rife and involves soaking an individual's feet in a saline bath through which an electrical current is passed. The device has been criticized for misleading consumers. The device, or something similar, is marketed under a wide variety of names.[1] due to the company responsible for developing the original device offers offers in-house web-design services for resellers.[2] As of October 15th, 2006, the Aqua Detox brand officially came under a new umbrella company called The Agenta Group[3]. # Manufacturer claims According to its manufacturer, the Aqua Detox system produces positive and negative ions, that "resonate through the body and stimulates the cells within it", claiming that this 'rebalances' cellular energy, allowing efficient performance and excretion of toxins that have accumulated within the tissues[2] and that 20 - 35 minutes of usage every second or third day causes toxins from throughout the body to be excreted from the 2000 pores of the feet [4] The manufacturer currently lacks evidence to demonstrate any detoxifying effect, but claims it is conducting a clinical trial to establish proof.[5]. # Criticisms Although the manufacturer does not make direct claims for Aqua Detox in the treatment or cure of disease, the Aqua Detox International was the subject of a British Advertising Standards Authority adjudication for April 6, 2005, specifically challenging the use of user testimonials which implied efficacy in serious disease, and challenges to the general efficacy of the device; both complaints were upheld, with the advertiser not addressing the efficacy of the device but promising to remove the misleading testimonials from their advertisements.[6] The marketer Miracle Beauty claims that the color of the bath indicates what areas have allegedly been cleansed of toxins: black for liver, orange for joints, green for gall bladder. [4] Aqua detox machines have iron electrodes that corrode to generate rust and tint the water brown when used to electrolyze saline in the footbath.[4] The different variations in color can be accounted by varying amount of salt added to the water and variations in the compositions of the electrodes.[4] An experiment with salt water and a car battery showed that the water will change color regardless, whether there are feet in the water or not, and that the composition the analyzed water was the same in both cases.[7] Barrett claims that it's nothing more than electrolysis, or rusting of the electrodes in the case of iron, and the change in color is being used by the manufacturers to mislead the consumers.[4] Aqua Detox has not been evaluated by the US Food and Drug Administration, and marketing materials related to the product carry a disclaimer to the effect that "it is not intended to diagnose, treat, cure, or prevent any disease." [2]	https://www.wikidoc.org/index.php/Aqua_Detox
a8150b51ed15705d256cbedcaf8cc6e3560e8281	wikidoc	Aquaretics	Aquaretics An aquaretic is a class of drug that is used to promote aquaresis. They are not strictly speaking diuretics, but are sometimes classified as such. Herbal aquaretics include adonis, agrimony, bearberry, buchu, dandelion, heartsease, hydrangea, lady's mantle, larch, and sassafras. These increase blood flow to the kidneys without increasing sodium and chloride resorption, thus causing an increase in urine whilst retaining electrolytes. However, the increase in intravascular fluid volume that they cause translates into an increase vascular resistance, and higher blood pressure. Synthetic aquaretics, a new class of drug, are V2 receptor antagonists, such as OPC-31260. These have been used in clinical trials as a treatment for Syndrome of inappropriate antidiuretic hormone (SIADH).	Aquaretics An aquaretic is a class of drug that is used to promote aquaresis. They are not strictly speaking diuretics, but are sometimes classified as such. Herbal aquaretics include adonis, agrimony, bearberry, buchu, dandelion, heartsease, hydrangea, lady's mantle, larch, and sassafras. These increase blood flow to the kidneys without increasing sodium and chloride resorption, thus causing an increase in urine whilst retaining electrolytes. However, the increase in intravascular fluid volume that they cause translates into an increase vascular resistance, and higher blood pressure.[1] Synthetic aquaretics, a new class of drug, are V2 receptor antagonists, such as OPC-31260. These have been used in clinical trials as a treatment for Syndrome of inappropriate antidiuretic hormone (SIADH).[2][3] Template:Drug-stub	https://www.wikidoc.org/index.php/Aquaretics
d891fa28a4de52db82c9ee1bb06ed300bde0d4c9	wikidoc	Cytarabine	Cytarabine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Cytarabine is an antineoplastic agent that is FDA approved for the treatment of acute non-lymphocytic leukemia of adults and children, acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia. Intrathecal administration of cytarabine injection is indicated for the prophylaxis and treatment of meningeal leukemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include thrombophlebitis, rash, hyperuricemia, anal inflammation, diarrhea, loss of apetite, nauseas, stomatitis, mouth ulceration, vomiting, decreased reticulocyte count, megaloblastic anemia, decreased liver function and fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Acute Non-Lymphocytic Leukemia - Induction: 100 mg/m2/day by continuous IV infusion (Days 1-7) or 100 mg/m2 IV every 12 hours (Days 1-7). ### Meningeal Leukemia - Dosage: doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cytarabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cytarabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Cytarabine FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cytarabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cytarabine in pediatric patients. # Contraindications - Cytarabine is contraindicated in those patients who are hypersensitive to the drug. # Warnings - Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leukocyte and platelet counts performed daily. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood. - Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses and hemorrhage secondary to thrombocytopenia). One case of anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine. - Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine) has been reported following some of the experimental cytarabine dose schedules. These reactions include reversible corneal toxicity, and hemorrhagic conjunctivitis, which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction including personality changes, somnolence and coma, usually reversible; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia, bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with experimental high dose therapy than with standard cytarabine treatment programs. If experimental high dose therapy is used, do not use a cytarabine injection containing benzyl alcohol. - Cases of cardiomyopathy with subsequent death has been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation. - A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. The outcome of this syndrome can be fatal. - Benzyl alcohol is contained in this product. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. - Two patients with childhood acute myelogenous leukemia who received intrathecal and intravenous cytarabine at conventional doses (in addition to a number of other concomitantly administered drugs) developed delayed progressive ascending paralysis resulting in death in one of the two patients. # Adverse Reactions ## Clinical Trials Experience ### Hematological Effects - Anemia - Leukopenia - Thrombocytopenia - Megaloblastosis - Reduced reticulocytes ### Infections Viral, bacterial, fungal, parasitic or saprophytic infections, in any location in the body may be associated with the use of cytarabine alone or in combination with other immunosuppressive agents following immunosuppressant doses that affect cellular or humoral immunity. These infections may be mild, but can be severe and at times fatal. ### Cytabarine Syndrome - Fever - Myalgia - Bone pain - Occasionally chest pain - Maculopapular rash - Conjunctivitis and malaise ### Cardiovascular effects - Cardiomyopathy - Pericarditis: < 0.1% of patients develop this adverse effect, between 2 - 3 days after initiating the therapy, symptoms lasting for 1-6 weeks . Symptoms include: Chest pain Dyspnea Pericardial effusion Pericardial friction rub Pulsus paradoxus Right ventricular diastolic collapse ST-Segment elevation on EKG - Chest pain - Dyspnea - Pericardial effusion - Pericardial friction rub - Pulsus paradoxus - Right ventricular diastolic collapse - ST-Segment elevation on EKG - Vasculitis: high-dose cytarabine causes small vessel necrotizing vasculitis. ### Dermatological effects - Alopecia - Dermatologic toxicity - Severe Henoch-Schönlein purpura - Rash - Toxic epidermal necrolysis ### Endocrine/metabolic Effects - Disorder of fluid and/or electrolyte: hypokalemia and hypocalcemia, specially when diarrhea is present. - Hyperuricemia: is a result of tumor lysis syndrome - Increased body temperature ### Gastrointestinal Effects - Gastrointestinal tract finding: nausea and vomiting are common agh high-dosis. GI bleeding has also been reported. - Pancreatitis Case report of a 36-year old male in therapy for 7 days with 200mg / m2 surface area / day . Case report of 2/30 Patients receiving cytarabine for leukemia and lymphoma in high doses (6.9 g IV every 12 hours for 11 doses and 5.25 g every 12 hours for 6 days). - Case report of a 36-year old male in therapy for 7 days with 200mg / m2 surface area / day . - Case report of 2/30 Patients receiving cytarabine for leukemia and lymphoma in high doses (6.9 g IV every 12 hours for 11 doses and 5.25 g every 12 hours for 6 days). - Parotiditis: Case report: 2/30 patients developed parotiditis with cytarabine 200 milligrams/square meter/day in continuous infusion for 7 days . - Case report: 2/30 patients developed parotiditis with cytarabine 200 milligrams/square meter/day in continuous infusion for 7 days . - Pseudomembranous enterocolitis Case report: 2 patients who developed Pseudomembranous Enterocolitis and as a consequence, needed subtotal colectomy. - Case report: 2 patients who developed Pseudomembranous Enterocolitis and as a consequence, needed subtotal colectomy. ### Hepatic Effects - Hepatotoxicity: It lead to jaundice and hyperbilirubinemia ### Immunological Effects - Anaphylaxis Case report of a 5 year-old patient receiving cytarabine . - Case report of a 5 year-old patient receiving cytarabine . - Immunosuppression ### Musculoeskeletal Effects - Rhabdomyolysis ### Neurologic Effects - Arachnoiditis - Aseptic meningitis Case report of a 8-year old patient in treatment for Acute Lymphoblastic Leukemia. - Case report of a 8-year old patient in treatment for Acute Lymphoblastic Leukemia. - Cranial nerve disorder Dysphagia Aphonia Diplopia Accessory nerve paralysis - Dysphagia - Aphonia - Diplopia - Accessory nerve paralysis - Neurological finding: Ataxia, dysphagia, nystagmus and decreased level of consciousness - Neuropathy - Neurotoxicity: causas cerebellar toxicity, characterized by: Dysarthria Ataxia Encephalopathy Seizures Coma - Dysarthria - Ataxia - Encephalopathy - Seizures - Coma - Paraplegia: Presents after intrathecal administration. - Paresthesia - Parkinsonism Case report of a 64 year-old patient in treatment for acute myelogenous leukemia with high dose cytarabine. - Case report of a 64 year-old patient in treatment for acute myelogenous leukemia with high dose cytarabine. - Pseudotumor cerebri ### Ophthalmic Effects - Conjunctivitis - Disorder of cornea: After one week with cytarabine treatment Tearing Foreign body sensation Photophobia Blurred vision - Tearing - Foreign body sensation - Photophobia - Blurred vision - Vision disorder Case report of a 31 year old patient after 2 weeks after receiving consolidation therapy with cytarabine 3 grams per square meter (g/m(2)) every 12 hours for 3 alternate days, developed vision loss. - Case report of a 31 year old patient after 2 weeks after receiving consolidation therapy with cytarabine 3 grams per square meter (g/m(2)) every 12 hours for 3 alternate days, developed vision loss. ### Urinary Tract Effects - Cystitis - Renal failure Case report: 45 year-old patient treated for hypoplastic myelodysplastic syndrome with low-dose cytarabine. - Case report: 45 year-old patient treated for hypoplastic myelodysplastic syndrome with low-dose cytarabine. - Urinary retention: its the least frequent of the urinary tract adverse effects ### Respiratory Effects - Acute respiratory distress syndrome - Pulmonary edema - Pulmonary toxicity ### Other - Hypersensitivity reaction - Sepsis ## Postmarketing Experience There is limited information regarding Cytarabine Postmarketing Experience in the drug label. # Drug Interactions - Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine or procarbazine. Steady-state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients may be considered as an alternative. - An in vitro interaction study between gentamicin and cytarabine showed a cytarabine related antagonism for the susceptibility of K. pneumoniae strains. This study suggests that in patients on cytarabine being treated with gentamicin for a K. pneumoniae infection, the lack of a prompt therapeutic response may indicate the need for reevaluation of antibacterial therapy. - Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy during therapy with cytarabine. This may be due to potential competitive inhibition of its uptake. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - A review of the literature has shown 32 reported cases where cytarabine was given during pregnancy, either alone or in combination with other cytotoxic agents. - Eighteen normal infants were delivered. Four of these had first trimester exposure. Five infants were premature or of low birth weight. Twelve of the 18 normal infants were followed up at ages ranging from six weeks to seven years, and showed no abnormalities. One apparently normal infant died at 90 days of gastroenteritis. - Two cases of congenital abnormalities have been reported, one with upper and lower distal limb defects, and the other with extremity and ear deformities. Both of these cases had first trimester exposure. - There were seven infants with various problems in the neonatal period, including pancytopenia; transient depression of the WBC, hematocrit or platelets; electrolyte abnormalities; transient eosinophilia; and one case of increased IgM levels and hyperpyrexia possibly due to sepsis. Six of the seven infants were also premature. The child with pancytopenia died at 21 days of sepsis. - Therapeutic abortions were done in five cases. Four fetuses were grossly normal, but one had an enlarged spleen and another showed Trisomy C chromosome abnormality in the chorionic tissue. - Because of the potential for abnormalities with cytotoxic therapy, particularly during the first trimester, a patient who is or who may become pregnant while on Cytarabine Injection should be apprised of the potential risk to the fetus and the advisability of pregnancy continuation. There is a definite, but considerably reduced risk if therapy is initiated during the second or third trimester. Although normal infants have been delivered to patients treated in all three trimesters of pregnancy, follow-up of such infants would be advisable. Pregnancy Category (AUS): D There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cytarabine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cytarabine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cytarabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use There is no FDA guidance on the use of Cytarabine in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Cytarabine in geriatric settings. ### Gender There is no FDA guidance on the use of Cytarabine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cytarabine with respect to specific racial populations. ### Renal Impairment - In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose cytarabine treatment. Use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor. ### Hepatic Impairment There is no FDA guidance on the use of Cytarabine in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Extensive chromosomal damage, including chromatid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported. ### Immunocompromised Patients There is no FDA guidance one the use of Cytarabine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Cytarabine Injection (non-preserved) can be administered by intravenous injection or infusion, subcutaneously, or intrathecally. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for IV infusion only. Intrathecal use of cytarabine requires the use of single-dose, unpreserved solutions only. - When cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician. ### Monitoring - Patients receiving Cytarabine Injection must be monitored closely. Frequent platelet and leukocyte counts and bone marrow examinations are mandatory. Consider suspending or modifying therapy when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte count under 1000/mm3. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped and reach lowest values after drug-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until "normal" peripheral blood values are attained may escape from control. - When large intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours post injection. This problem tends to be less severe when the drug is infused. - The human liver apparently detoxifies a substantial fraction of an administered dose. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose cytarabine treatment. Use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor. - Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving Cytarabine Injection. - Like other cytotoxic drugs, Cytarabine Injection may induce hyperuricemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem. - Acute pancreatitis has been reported to occur in a patient receiving cytarabine by continuous infusion and in patients being treated with cytarabine who have had prior treatment with L-asparaginase. # IV Compatibility If used intrathecally, do not use a solution containing benzyl alcohol. This pharmacy bulk package is not intended to be used for the preparation of intrathecal doses. # Overdosage - There is no antidote for cytarabine over dosage. Doses of 4.5 g/m2 by intravenous infusion over 1 hour every 12 hours for 12 doses has caused an unacceptable increase in irreversible CNS toxicity and death. - Single doses as high as 3 g/m2 have been administered by rapid intravenous infusion without apparent toxicity. # Pharmacology ## Mechanism of Action - Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported. Extensive chromosomal damage, including chromatid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported. Deoxycytidine prevents or delays (but does not reverse) the cytotoxic activity. ## Structure Cytarabine is chemically 4-amino-l- β-Darabinofuranosyl- 2(lH)-pyrimidinone. ## Pharmacodynamics There is limited information regarding Cytarabine Pharmacodynamics in the drug label. ## Pharmacokinetics - Cytarabine is rapidly metabolized and is not effective orally; less than 20 percent of the orally administered dose is absorbed from the gastrointestinal tract. - Following rapid intravenous injection of cytarabine, labeled with tritium, the disappearance from plasma is biphasic. There is an initial distributive phase with a half-life of about 10 minutes, followed by a second elimination phase with a half-life of about 1 to 3 hours. After the distributive phase, more than 80 percent of plasma radioactivity can be accounted for by the inactive metabolite 1-β-D-arabinofuranosyluracil (ara-U). Within 24 hours about 80 percent of the administered radioactivity can be recovered in the urine, approximately 90 percent of which is excreted as ara-U. - Relatively constant plasma levels can be achieved by continuous intravenous infusion. - After subcutaneous or intramuscular administration of cytarabine labeled with tritium, peak-plasma levels of radioactivity are achieved about 20 to 60 minutes after injection and are considerably lower than those after intravenous administration. - Cerebrospinal fluid levels of cytarabine are low in comparison to plasma levels after single intravenous injection. However, in one patient in whom cerebrospinal fluid levels are examined after 2 hours of constant intravenous infusion, levels approached 40 percent of the steady state plasma level. With intrathecal administration, levels of cytarabine in the cerebrospinal fluid declined with a first order half-life of about 2 hours. Because cerebrospinal fluid levels of deaminase are low, little conversion to ara-U was observed. ## Nonclinical Toxicology There is limited information regarding Cytarabine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Cytarabine Clinical Studies in the drug label. # How Supplied Cytarabine Injection, PHARMACY BULK PACKAGE. Sterile, Isotonic Solution. Preservative, Free. NDC No. 0069-0154-01.Cytarabine Injection 1000 mg in a 50 mL, (20 mg/mL) flip-top vial (brown cap), packaged individually. ## Storage Store between, 20° - 25°C (68° - 77°F). . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Cytarabine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Cytarabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tarabine PFS - Cytosar - Cytosar-U # Look-Alike Drug Names There is limited information regarding Cytarabine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cytarabine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Cytarabine is an antineoplastic agent that is FDA approved for the treatment of acute non-lymphocytic leukemia of adults and children, acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia. Intrathecal administration of cytarabine injection is indicated for the prophylaxis and treatment of meningeal leukemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include thrombophlebitis, rash, hyperuricemia, anal inflammation, diarrhea, loss of apetite, nauseas, stomatitis, mouth ulceration, vomiting, decreased reticulocyte count, megaloblastic anemia, decreased liver function and fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Acute Non-Lymphocytic Leukemia - Induction: 100 mg/m2/day by continuous IV infusion (Days 1-7) or 100 mg/m2 IV every 12 hours (Days 1-7). ### Meningeal Leukemia - Dosage: doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cytarabine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cytarabine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Cytarabine FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cytarabine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cytarabine in pediatric patients. # Contraindications - Cytarabine is contraindicated in those patients who are hypersensitive to the drug. # Warnings - Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leukocyte and platelet counts performed daily. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood. - Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses and hemorrhage secondary to thrombocytopenia). One case of anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine. - Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine) has been reported following some of the experimental cytarabine dose schedules. These reactions include reversible corneal toxicity, and hemorrhagic conjunctivitis, which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction including personality changes, somnolence and coma, usually reversible; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia, bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with experimental high dose therapy than with standard cytarabine treatment programs. If experimental high dose therapy is used, do not use a cytarabine injection containing benzyl alcohol. - Cases of cardiomyopathy with subsequent death has been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation. - A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. The outcome of this syndrome can be fatal. - Benzyl alcohol is contained in this product. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. - Two patients with childhood acute myelogenous leukemia who received intrathecal and intravenous cytarabine at conventional doses (in addition to a number of other concomitantly administered drugs) developed delayed progressive ascending paralysis resulting in death in one of the two patients. # Adverse Reactions ## Clinical Trials Experience ### Hematological Effects - Anemia - Leukopenia - Thrombocytopenia - Megaloblastosis - Reduced reticulocytes ### Infections Viral, bacterial, fungal, parasitic or saprophytic infections, in any location in the body may be associated with the use of cytarabine alone or in combination with other immunosuppressive agents following immunosuppressant doses that affect cellular or humoral immunity. These infections may be mild, but can be severe and at times fatal. ### Cytabarine Syndrome - Fever - Myalgia - Bone pain - Occasionally chest pain - Maculopapular rash - Conjunctivitis and malaise ### Cardiovascular effects - Cardiomyopathy - Pericarditis: < 0.1% of patients develop this adverse effect, between 2 - 3 days after initiating the therapy, symptoms lasting for 1-6 weeks [1] [2] [3]. Symptoms include: Chest pain Dyspnea Pericardial effusion Pericardial friction rub Pulsus paradoxus Right ventricular diastolic collapse ST-Segment elevation on EKG - Chest pain - Dyspnea - Pericardial effusion - Pericardial friction rub - Pulsus paradoxus - Right ventricular diastolic collapse - ST-Segment elevation on EKG - Vasculitis: high-dose cytarabine causes small vessel necrotizing vasculitis[4]. ### Dermatological effects - Alopecia - Dermatologic toxicity[5] - Severe Henoch-Schönlein purpura[6] - Rash - Toxic epidermal necrolysis[7] ### Endocrine/metabolic Effects - Disorder of fluid and/or electrolyte: hypokalemia and hypocalcemia, specially when diarrhea is present[8]. - Hyperuricemia: is a result of tumor lysis syndrome[9] - Increased body temperature[10] ### Gastrointestinal Effects - Gastrointestinal tract finding: nausea and vomiting are common agh high-dosis[9]. GI bleeding has also been reported[8]. - Pancreatitis Case report of a 36-year old male in therapy for 7 days with 200mg / m2 surface area / day [11]. Case report of 2/30 Patients receiving cytarabine for leukemia and lymphoma in high doses (6.9 g IV every 12 hours for 11 doses and 5.25 g every 12 hours for 6 days)[12]. - Case report of a 36-year old male in therapy for 7 days with 200mg / m2 surface area / day [11]. - Case report of 2/30 Patients receiving cytarabine for leukemia and lymphoma in high doses (6.9 g IV every 12 hours for 11 doses and 5.25 g every 12 hours for 6 days)[12]. - Parotiditis: Case report: 2/30 patients developed parotiditis with cytarabine 200 milligrams/square meter/day in continuous infusion for 7 days [13]. - Case report: 2/30 patients developed parotiditis with cytarabine 200 milligrams/square meter/day in continuous infusion for 7 days [13]. - Pseudomembranous enterocolitis Case report: 2 patients who developed Pseudomembranous Enterocolitis and as a consequence, needed subtotal colectomy[14]. - Case report: 2 patients who developed Pseudomembranous Enterocolitis and as a consequence, needed subtotal colectomy[14]. ### Hepatic Effects - Hepatotoxicity[15]: It lead to jaundice and hyperbilirubinemia ### Immunological Effects - Anaphylaxis Case report of a 5 year-old patient receiving cytarabine [16]. - Case report of a 5 year-old patient receiving cytarabine [16]. - Immunosuppression ### Musculoeskeletal Effects - Rhabdomyolysis[17] ### Neurologic Effects - Arachnoiditis[18] - Aseptic meningitis Case report of a 8-year old patient in treatment for Acute Lymphoblastic Leukemia[19]. - Case report of a 8-year old patient in treatment for Acute Lymphoblastic Leukemia[19]. - Cranial nerve disorder Dysphagia Aphonia Diplopia Accessory nerve paralysis - Dysphagia - Aphonia - Diplopia - Accessory nerve paralysis - Neurological finding: Ataxia[20], dysphagia, nystagmus[21] and decreased level of consciousness[22] - Neuropathy [23] - Neurotoxicity[22]: causas cerebellar toxicity[24][25], characterized by: Dysarthria Ataxia Encephalopathy Seizures Coma - Dysarthria - Ataxia - Encephalopathy - Seizures - Coma - Paraplegia: Presents after intrathecal administration[26]. - Paresthesia - Parkinsonism Case report of a 64 year-old patient in treatment for acute myelogenous leukemia with high dose cytarabine[27]. - Case report of a 64 year-old patient in treatment for acute myelogenous leukemia with high dose cytarabine[27]. - Pseudotumor cerebri[28] ### Ophthalmic Effects - Conjunctivitis - Disorder of cornea[29]: After one week with cytarabine treatment Tearing Foreign body sensation Photophobia Blurred vision - Tearing - Foreign body sensation - Photophobia - Blurred vision - Vision disorder Case report of a 31 year old patient after 2 weeks after receiving consolidation therapy with cytarabine 3 grams per square meter (g/m(2)) every 12 hours for 3 alternate days, developed vision loss[30]. - Case report of a 31 year old patient after 2 weeks after receiving consolidation therapy with cytarabine 3 grams per square meter (g/m(2)) every 12 hours for 3 alternate days, developed vision loss[30]. ### Urinary Tract Effects - Cystitis[31] - Renal failure Case report: 45 year-old patient treated for hypoplastic myelodysplastic syndrome with low-dose cytarabine[32]. - Case report: 45 year-old patient treated for hypoplastic myelodysplastic syndrome with low-dose cytarabine[32]. - Urinary retention: its the least frequent of the urinary tract adverse effects ### Respiratory Effects - Acute respiratory distress syndrome - Pulmonary edema - Pulmonary toxicity ### Other - Hypersensitivity reaction - Sepsis ## Postmarketing Experience There is limited information regarding Cytarabine Postmarketing Experience in the drug label. # Drug Interactions - Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine or procarbazine. Steady-state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients may be considered as an alternative. - An in vitro interaction study between gentamicin and cytarabine showed a cytarabine related antagonism for the susceptibility of K. pneumoniae strains. This study suggests that in patients on cytarabine being treated with gentamicin for a K. pneumoniae infection, the lack of a prompt therapeutic response may indicate the need for reevaluation of antibacterial therapy. - Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy during therapy with cytarabine. This may be due to potential competitive inhibition of its uptake. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - A review of the literature has shown 32 reported cases where cytarabine was given during pregnancy, either alone or in combination with other cytotoxic agents. - Eighteen normal infants were delivered. Four of these had first trimester exposure. Five infants were premature or of low birth weight. Twelve of the 18 normal infants were followed up at ages ranging from six weeks to seven years, and showed no abnormalities. One apparently normal infant died at 90 days of gastroenteritis. - Two cases of congenital abnormalities have been reported, one with upper and lower distal limb defects, and the other with extremity and ear deformities. Both of these cases had first trimester exposure. - There were seven infants with various problems in the neonatal period, including pancytopenia; transient depression of the WBC, hematocrit or platelets; electrolyte abnormalities; transient eosinophilia; and one case of increased IgM levels and hyperpyrexia possibly due to sepsis. Six of the seven infants were also premature. The child with pancytopenia died at 21 days of sepsis. - Therapeutic abortions were done in five cases. Four fetuses were grossly normal, but one had an enlarged spleen and another showed Trisomy C chromosome abnormality in the chorionic tissue. - Because of the potential for abnormalities with cytotoxic therapy, particularly during the first trimester, a patient who is or who may become pregnant while on Cytarabine Injection should be apprised of the potential risk to the fetus and the advisability of pregnancy continuation. There is a definite, but considerably reduced risk if therapy is initiated during the second or third trimester. Although normal infants have been delivered to patients treated in all three trimesters of pregnancy, follow-up of such infants would be advisable. Pregnancy Category (AUS): D There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cytarabine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cytarabine during labor and delivery. ### Nursing Mothers - It is not known whether this drug is excreted in human milk: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cytarabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use There is no FDA guidance on the use of Cytarabine in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Cytarabine in geriatric settings. ### Gender There is no FDA guidance on the use of Cytarabine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cytarabine with respect to specific racial populations. ### Renal Impairment - In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose cytarabine treatment. Use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor. ### Hepatic Impairment There is no FDA guidance on the use of Cytarabine in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Extensive chromosomal damage, including chromatid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported. ### Immunocompromised Patients There is no FDA guidance one the use of Cytarabine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Cytarabine Injection (non-preserved) can be administered by intravenous injection or infusion, subcutaneously, or intrathecally. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for IV infusion only. Intrathecal use of cytarabine requires the use of single-dose, unpreserved solutions only. - When cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician. ### Monitoring - Patients receiving Cytarabine Injection must be monitored closely. Frequent platelet and leukocyte counts and bone marrow examinations are mandatory. Consider suspending or modifying therapy when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte count under 1000/mm3. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped and reach lowest values after drug-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until "normal" peripheral blood values are attained may escape from control. - When large intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours post injection. This problem tends to be less severe when the drug is infused. - The human liver apparently detoxifies a substantial fraction of an administered dose. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose cytarabine treatment. Use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor. - Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving Cytarabine Injection. - Like other cytotoxic drugs, Cytarabine Injection may induce hyperuricemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem. - Acute pancreatitis has been reported to occur in a patient receiving cytarabine by continuous infusion and in patients being treated with cytarabine who have had prior treatment with L-asparaginase. # IV Compatibility If used intrathecally, do not use a solution containing benzyl alcohol. This pharmacy bulk package is not intended to be used for the preparation of intrathecal doses. # Overdosage - There is no antidote for cytarabine over dosage. Doses of 4.5 g/m2 by intravenous infusion over 1 hour every 12 hours for 12 doses has caused an unacceptable increase in irreversible CNS toxicity and death. - Single doses as high as 3 g/m2 have been administered by rapid intravenous infusion without apparent toxicity. # Pharmacology ## Mechanism of Action - Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported. Extensive chromosomal damage, including chromatid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported. Deoxycytidine prevents or delays (but does not reverse) the cytotoxic activity. ## Structure Cytarabine is chemically 4-amino-l- β-Darabinofuranosyl- 2(lH)-pyrimidinone. ## Pharmacodynamics There is limited information regarding Cytarabine Pharmacodynamics in the drug label. ## Pharmacokinetics - Cytarabine is rapidly metabolized and is not effective orally; less than 20 percent of the orally administered dose is absorbed from the gastrointestinal tract. - Following rapid intravenous injection of cytarabine, labeled with tritium, the disappearance from plasma is biphasic. There is an initial distributive phase with a half-life of about 10 minutes, followed by a second elimination phase with a half-life of about 1 to 3 hours. After the distributive phase, more than 80 percent of plasma radioactivity can be accounted for by the inactive metabolite 1-β-D-arabinofuranosyluracil (ara-U). Within 24 hours about 80 percent of the administered radioactivity can be recovered in the urine, approximately 90 percent of which is excreted as ara-U. - Relatively constant plasma levels can be achieved by continuous intravenous infusion. - After subcutaneous or intramuscular administration of cytarabine labeled with tritium, peak-plasma levels of radioactivity are achieved about 20 to 60 minutes after injection and are considerably lower than those after intravenous administration. - Cerebrospinal fluid levels of cytarabine are low in comparison to plasma levels after single intravenous injection. However, in one patient in whom cerebrospinal fluid levels are examined after 2 hours of constant intravenous infusion, levels approached 40 percent of the steady state plasma level. With intrathecal administration, levels of cytarabine in the cerebrospinal fluid declined with a first order half-life of about 2 hours. Because cerebrospinal fluid levels of deaminase are low, little conversion to ara-U was observed. ## Nonclinical Toxicology There is limited information regarding Cytarabine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Cytarabine Clinical Studies in the drug label. # How Supplied Cytarabine Injection, PHARMACY BULK PACKAGE. Sterile, Isotonic Solution. Preservative, Free. NDC No. 0069-0154-01.Cytarabine Injection 1000 mg in a 50 mL, (20 mg/mL) flip-top vial (brown cap), packaged individually. ## Storage Store between, 20° - 25°C (68° - 77°F). [See USP Controlled Room Temperature]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Cytarabine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Cytarabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Tarabine PFS - Cytosar - Cytosar-U # Look-Alike Drug Names There is limited information regarding Cytarabine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ara-C
49c0f3d081c6f1de2c5431594f0eddc7ab117c43	wikidoc	Arcobacter	Arcobacter # Overview Arcobacter is a genus of Gram-negative, spiral-shaped bacteria in the epsilonproteobacteria class. It shows an unusually wide range of habitats, and some species can be human and animal pathogens. Species of the genus Arcobacter are found in both animal and environmental sources, making it unique among the epsilonproteobacteria. This genus currently consists of five species: A. butzleri, A. cryaerophilus, A. skirrowii, A. nitrofigilis, and A. sulfidicus, although several other potential novel species have recently been described from varying environments. Three of these five known species are pathogenic. Members of this genus were first isolated in 1977 from aborted bovine fetuses. They are aerotolerant Campylobacter-like organisms, previously classified as Campylobacter. The Arcobacter genus, in fact, was created as recently as 1992. Although they are similar to this other genus, Arcobacter species can grow at lower temperatures than Campylobacter as well as in the air, which Campylobacter cannot. The name Arcobacter is derived from the Latin "arcus" meaning "bow" and the Greek "bacter" meaning "rod", and should be understood to mean "bow-shaped rod" or "curved rod". This is a reference to the characteristic curved shaped that most Arcobacter cells possess. # Pathogenicity Arcobacter species have been discovered as both animal and human pathogens within the past decade, thanks to improvements in isolation techniques. Up to now, little is known about the mechanisms of pathogenicity or potential virulence factors of Arcobacter spp. Since no routine diagnostic of these bacteria has been performed, the global prevalence of Arcobacter infection is rather underestimated and the exact routes of transmission are unknown. There is evidence that livestock animals may be a significant reservoir of Arcobacter, and over the last few years, the presence of these organisms in raw meat products as well as in surface and ground water has received increasing attention. In humans, A. butzleri and, less commonly, A. cryaerophilus have been linked to enteritis and occasionally bacteremia. Symptoms of A. butzleri infections include diarrhea associated with abdominal pain, nausea, and vomiting or fever. Studies of patients infected with A. butzleri have demonstrated that without treatment, symptoms endured for a very variable amount of time, from two days to several weeks. When antimicrobial therapies were administered, the infection was eradicated within a few days, and all strains in the study were found to be susceptible to the antibiotics given. A third species, A. skirrowii, has also recently been isolated from a patient with chronic diarrhea. Although the microbiological and clinical features of Arcobacter are not yet well defined, initial studies of A. butzleri suggest that these bacteria display similar microbiological and clinical features as C. jejuni, but are more associated with a persistent, watery diarrhea than with the bloody diarrhea associated with C. jejuni. Recent studies suggest that A. butzleri induces epithelial barrier dysfunction by changes in tight junction proteins and induction of epithelial apoptosis. Based on this model, the virulence of A. butzleri seems to have two phases. An initial effect on tight junctions was observed first, followed by a late effect on cytotoxicity because of necrosis and induction of apoptosis. # Nonpathogenic strains A. nitrofigilis is a nitrogen-fixing bacterium isolated from the roots of the salt marsh plant Spartina alterniflora. A. sulfidicus is an obligate microaerophile that oxidizes sulfides and is an autotrophic producer of filamentous sulfur. Large populations of this bacterium produce mats of this solid, white sulfur filament. These mats are useful in anchoring the bacteria to rocky surfaces in the face of flowing subsurface hydrothermal fluids, as well as providing important carpeting around hydrothermal vents that attracts other animals to that site and encourages them to settle and grow. One interesting potential novel Arcobacter species, designated LA31BT, was isolated from water collected from a hypersaline lagoon. Preliminary characterization based on 16S rRNA gene sequence analysis showed that LA31BT shared 94% identity with A. nitrofigilis, the type species of the genus, and taxonomic studies confirmed the phylogenetic affiliation of strain LA31BT to the genus Arcobacter. Other analytical methods, however, showed that LA31BT was distinct from all recognized Arcobacter species. Most notably and of interest, LA31BT was found to be an obligate halophile, a trait not found among recognized Arcobacter species. Another unusual Arcobacter species, designated strain CAB, was isolated from marine sediment and found to have the capacity to grow via perchlorate reduction, the only member of the epsilonproteobacteria in pure culture to possess this rare metabolism. Unlike most Arcobacter species, CAB was found to degrade carbohydrates, including fructose and catechol, and its cells often lacked the distinctive curvature typical of the Arcobacter genus.	Arcobacter Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Arcobacter is a genus of Gram-negative, spiral-shaped bacteria in the epsilonproteobacteria class.[1] It shows an unusually wide range of habitats, and some species can be human and animal pathogens.[1][2] Species of the genus Arcobacter are found in both animal and environmental sources, making it unique among the epsilonproteobacteria.[3] This genus currently consists of five species: A. butzleri, A. cryaerophilus, A. skirrowii, A. nitrofigilis, and A. sulfidicus, although several other potential novel species have recently been described from varying environments.[3][4] Three of these five known species are pathogenic.[4] Members of this genus were first isolated in 1977 from aborted bovine fetuses. They are aerotolerant Campylobacter-like organisms, previously classified as Campylobacter.[5] The Arcobacter genus, in fact, was created as recently as 1992.[6] Although they are similar to this other genus, Arcobacter species can grow at lower temperatures than Campylobacter as well as in the air, which Campylobacter cannot.[5] The name Arcobacter is derived from the Latin "arcus" meaning "bow" and the Greek "bacter" meaning "rod", and should be understood to mean "bow-shaped rod" or "curved rod". This is a reference to the characteristic curved shaped that most Arcobacter cells possess.[7] # Pathogenicity Arcobacter species have been discovered as both animal and human pathogens within the past decade, thanks to improvements in isolation techniques.[5] Up to now, little is known about the mechanisms of pathogenicity or potential virulence factors of Arcobacter spp.[8] Since no routine diagnostic of these bacteria has been performed, the global prevalence of Arcobacter infection is rather underestimated and the exact routes of transmission are unknown.[9] There is evidence that livestock animals may be a significant reservoir of Arcobacter, and over the last few years, the presence of these organisms in raw meat products as well as in surface and ground water has received increasing attention.[8] In humans, A. butzleri and, less commonly, A. cryaerophilus have been linked to enteritis and occasionally bacteremia.[5] Symptoms of A. butzleri infections include diarrhea associated with abdominal pain, nausea, and vomiting or fever.[5] Studies of patients infected with A. butzleri have demonstrated that without treatment, symptoms endured for a very variable amount of time, from two days to several weeks.[6] When antimicrobial therapies were administered, the infection was eradicated within a few days, and all strains in the study were found to be susceptible to the antibiotics given.[6] A third species, A. skirrowii, has also recently been isolated from a patient with chronic diarrhea.[5] Although the microbiological and clinical features of Arcobacter are not yet well defined, initial studies of A. butzleri suggest that these bacteria display similar microbiological and clinical features as C. jejuni, but are more associated with a persistent, watery diarrhea than with the bloody diarrhea associated with C. jejuni.[5] Recent studies suggest that A. butzleri induces epithelial barrier dysfunction by changes in tight junction proteins and induction of epithelial apoptosis.[9] Based on this model, the virulence of A. butzleri seems to have two phases. An initial effect on tight junctions was observed first, followed by a late effect on cytotoxicity because of necrosis and induction of apoptosis.[9] # Nonpathogenic strains A. nitrofigilis is a nitrogen-fixing bacterium isolated from the roots of the salt marsh plant Spartina alterniflora.[4] A. sulfidicus is an obligate microaerophile that oxidizes sulfides and is an autotrophic producer of filamentous sulfur.[4] Large populations of this bacterium produce mats of this solid, white sulfur filament.[10] These mats are useful in anchoring the bacteria to rocky surfaces in the face of flowing subsurface hydrothermal fluids, as well as providing important carpeting around hydrothermal vents that attracts other animals to that site and encourages them to settle and grow.[10] One interesting potential novel Arcobacter species, designated LA31BT, was isolated from water collected from a hypersaline lagoon.[3] Preliminary characterization based on 16S rRNA gene sequence analysis showed that LA31BT shared 94% identity with A. nitrofigilis, the type species of the genus, and taxonomic studies confirmed the phylogenetic affiliation of strain LA31BT to the genus Arcobacter.[3] Other analytical methods, however, showed that LA31BT was distinct from all recognized Arcobacter species. Most notably and of interest, LA31BT was found to be an obligate halophile, a trait not found among recognized Arcobacter species.[3] Another unusual Arcobacter species, designated strain CAB, was isolated from marine sediment and found to have the capacity to grow via perchlorate reduction, the only member of the epsilonproteobacteria in pure culture to possess this rare metabolism.[11] Unlike most Arcobacter species, CAB was found to degrade carbohydrates, including fructose and catechol, and its cells often lacked the distinctive curvature typical of the Arcobacter genus.[11]	https://www.wikidoc.org/index.php/Arcobacter
939c4224777db71cfb8f64ce7c1918fb4061ee5e	wikidoc	Etoricoxib	Etoricoxib # Overview Etoricoxib (brand name Arcoxia worldwide; also Algix and Tauxib in Italy) is a new COX-2 selective inhibitor (approx. 106.0 times more selective for COX-2 inhibition over COX-1) from Merck & Co. Doses are 60, 90 mg/day for chronic pain and 120 mg/day for acute pain. Currently it is approved in more than 60 countries worldwide but not in the US, where the Food and Drug Administration (FDA) require additional safety and efficacy data for etoricoxib before it will issue approval. Current therapeutic indications are: treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout. Note that approved indications differ by country. Like any other COX-2 selective inhibitor, Etoricoxib selectively inhibits isoform 2 of cyclo-oxigenase enzyme (COX-2). This reduces the generation of prostaglandins (PGs) from arachidonic acid. Among the different functions exerted by PGs, their role in the inflammation cascade should be highlighted. COX-2 selective inhibitor (aka "COXIB") showed less marked activity on type 1 cycloxigenase compared to traditional non-steroidal anti-inflammatory drugs (NSAID). This reduced activity is the cause of reduced gastrointestinal toxicity, as demonstrated in several large clinical trials performed with different COXIB (see below links on NEJM and The Lancet). Some clinical trials and meta-analysis showed that treatment with COXIB led to increased incidence of adverse cardiovascular events compared to placebo. Because of these results, some molecules were withdrawn from the market (Rofecoxib, September 2004 and Valdecoxib, April 2005). In addition, the FDA and EMEA (USA and European Community Health Authorities respectively) started a revision process of the entire class of both NSAID and COX-2 inhibitors. FDA concluded its revision on April 6, 2005: the final document can be found at: EMEA concluded its revision on June 27, 2005: the final document can be found at: On April 27, 2007, the Food and Drug Administration issued Merck a "non-approvable letter" for Arcoxia. The letter said Merck needs to provide more test results showing that Arcoxia's benefits outweigh its risks before it has another chance of getting approved.	Etoricoxib # Overview Etoricoxib (brand name Arcoxia worldwide; also Algix and Tauxib in Italy) is a new COX-2 selective inhibitor (approx. 106.0 times more selective for COX-2 inhibition over COX-1) from Merck & Co. Doses are 60, 90 mg/day for chronic pain and 120 mg/day for acute pain. Currently it is approved in more than 60 countries worldwide but not in the US, where the Food and Drug Administration (FDA) require additional safety and efficacy data for etoricoxib before it will issue approval. Current therapeutic indications are: treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout. Note that approved indications differ by country. Like any other COX-2 selective inhibitor, Etoricoxib selectively inhibits isoform 2 of cyclo-oxigenase enzyme (COX-2). This reduces the generation of prostaglandins (PGs) from arachidonic acid. Among the different functions exerted by PGs, their role in the inflammation cascade should be highlighted. COX-2 selective inhibitor (aka "COXIB") showed less marked activity on type 1 cycloxigenase compared to traditional non-steroidal anti-inflammatory drugs (NSAID). This reduced activity is the cause of reduced gastrointestinal toxicity, as demonstrated in several large clinical trials performed with different COXIB (see below links on NEJM and The Lancet). Some clinical trials and meta-analysis showed that treatment with COXIB led to increased incidence of adverse cardiovascular events compared to placebo. Because of these results, some molecules were withdrawn from the market (Rofecoxib, September 2004 and Valdecoxib, April 2005). In addition, the FDA and EMEA (USA and European Community Health Authorities respectively) started a revision process of the entire class of both NSAID and COX-2 inhibitors. FDA concluded its revision on April 6, 2005: the final document can be found at: http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf EMEA concluded its revision on June 27, 2005: the final document can be found at: http://www.emea.europa.eu/pdfs/human/press/pr/20776605en.pdf On April 27, 2007, the Food and Drug Administration issued Merck a "non-approvable letter" for Arcoxia. The letter said Merck needs to provide more test results showing that Arcoxia's benefits outweigh its risks before it has another chance of getting approved. # External links - European Medicines Agency (EMEA) - Homepage - [1] - US Food and Drug Administration (FDA) - Homepage - [2] - (VIGOR study on The New England Journal of Medicine - NEJM) - (MEDAL study on The Lancet) Template:Pharma-stub nl:Etoricoxib Template:WH Template:WS Template:Jb1	https://www.wikidoc.org/index.php/Arcoxia
35ce0899ebe1d0efda74f1d8f74ba26f08b0aa73	wikidoc	Arenavirus	Arenavirus # Overview The Arenaviridae are a family of viruses whose members are generally associated with rodent-transmitted diseases in humans. Each virus usually is associated with a particular rodent host species in which it is maintained. Arenavirus infections are relatively common in humans in some areas of the world and can cause severe illnesses. ## Arenaviridae - Lassa virus belongs to Arenaviridae . - The Arenaviridae are a family of viruses whose members are generally associated with rodent-transmitted diseases in humans. Each virus usually is associated with a particular rodent host species in which it is maintained. Arenavirus infections are relatively common in humans in some areas of the world and can cause severe illnesses. - The virus particles are spherical and have an average diameter of 110-130 nanometers. All are enveloped in a lipid (fat) membrane. Viewed in cross-section, they show grainy particles that are ribosomes acquired from their host cells. It is this characteristic that gave them their name, derived from the Latin "arena", which means "sandy". Their genome, or genetic material, is composed of RNA only, and while their replication strategy is not completely understood, we know that new viral particles, called virions, are created by budding from the surface of their hosts' cells. ## History of Arenaviridae - The first Arenavirus, Lymphocytic choriomeningitis virus (LCMV), was isolated in 1933 during a study of an epidemic of St. Louis encephalitis. Although not the cause of the outbreak, LCMV was found to be a cause of aseptic (nonbacterial) meningitis. By the 1960s, several similar viruses had been discovered and they were classified into the new family Arenaviridae. Since Tacaribe virus was found in 1956, new Arenavirus have been discovered on the average of every one to three years. A number of Arenavirus have been isolated in rodents only, but few cause hemorrhagic disease. Junin virus, isolated in 1958, was the first of these to be recognized. This virus causes Argentine hemorrhagic fever in a limited agrigultural area of the pampas in Argentina. Several years later, in 1963, in the remote savannas of the Beni province of Bolivia, Machupo virus was isolated. The next member of the virus family to be associated with an outbreak of human illness was Lassa virus in Nigeria in 1969. The most recent additions to these human pathogenic viruses were Guanarito detected in Venezuela in 1989, Sabia in Brazil in 1993, Chapare in Bolivia in 2004, and Lujo in South Africa in 2008. Arenavirus is a genus of virus. The type species is Lymphocytic choriomeningitis virus (LCMV); it also includes the species responsible for Lassa fever. Arena comes from the Latin root meaning sand. Arenaviruses can be divided into two serogroups, which differ genetically and by geographical distribution: - LCMV-Lassa virus (Old World) complex: Ippy virus Lassa virus Lymphocytic choriomeningitis virus Mobala virus Mopeia virus - Ippy virus - Lassa virus - Lymphocytic choriomeningitis virus - Mobala virus - Mopeia virus - Tacaribe virus (New World) complex: Amapari virus Flexal virus Guanarito virus Junin virus Latino virus Machupo virus Oliveros virus Paraná virus Pichinde virus Pirital virus Sabiá virus Tacaribe virus Tamiami virus Whitewater Arroyo virus - Amapari virus - Flexal virus - Guanarito virus - Junin virus - Latino virus - Machupo virus - Oliveros virus - Paraná virus - Pichinde virus - Pirital virus - Sabiá virus - Tacaribe virus - Tamiami virus - Whitewater Arroyo virus Some arenaviruses are zoonotic pathogens and are generally associated with rodent-transmitted disease in humans. Each virus usually is associated with a particular rodent host species in which it is maintained. The virus particles are spherical and have an average diameter of 110-130 nanometers. All are enveloped in a lipid membrane. Viewed in cross-section, they show grainy particles that are ribosomes acquired from their host cells. It is this characteristic that gave them their name, derived from the Latin "arena," which means "sandy." Their genome, or genetic material, is composed of RNA only, and while their replication strategy is not completely understood, we know that new viral particles, called virions, are created by budding from the surface of their hosts’ cells.	Arenavirus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The Arenaviridae are a family of viruses whose members are generally associated with rodent-transmitted diseases in humans. Each virus usually is associated with a particular rodent host species in which it is maintained. Arenavirus infections are relatively common in humans in some areas of the world and can cause severe illnesses. ## Arenaviridae - Lassa virus belongs to Arenaviridae [1]. - The Arenaviridae are a family of viruses whose members are generally associated with rodent-transmitted diseases in humans. Each virus usually is associated with a particular rodent host species in which it is maintained. Arenavirus infections are relatively common in humans in some areas of the world and can cause severe illnesses. - The virus particles are spherical and have an average diameter of 110-130 nanometers. All are enveloped in a lipid (fat) membrane. Viewed in cross-section, they show grainy particles that are ribosomes acquired from their host cells. It is this characteristic that gave them their name, derived from the Latin "arena", which means "sandy". Their genome, or genetic material, is composed of RNA only, and while their replication strategy is not completely understood, we know that new viral particles, called virions, are created by budding from the surface of their hosts' cells. ## History of Arenaviridae - The first Arenavirus, Lymphocytic choriomeningitis virus (LCMV), was isolated in 1933 during a study of an epidemic of St. Louis encephalitis. Although not the cause of the outbreak, LCMV was found to be a cause of aseptic (nonbacterial) meningitis. By the 1960s, several similar viruses had been discovered and they were classified into the new family Arenaviridae. Since Tacaribe virus was found in 1956, new Arenavirus have been discovered on the average of every one to three years. A number of Arenavirus have been isolated in rodents only, but few cause hemorrhagic disease. Junin virus, isolated in 1958, was the first of these to be recognized. This virus causes Argentine hemorrhagic fever in a limited agrigultural area of the pampas in Argentina. Several years later, in 1963, in the remote savannas of the Beni province of Bolivia, Machupo virus was isolated. The next member of the virus family to be associated with an outbreak of human illness was Lassa virus in Nigeria in 1969. The most recent additions to these human pathogenic viruses were Guanarito detected in Venezuela in 1989, Sabia in Brazil in 1993, Chapare in Bolivia in 2004, and Lujo in South Africa in 2008. Arenavirus is a genus of virus. The type species is Lymphocytic choriomeningitis virus (LCMV); it also includes the species responsible for Lassa fever. Arena comes from the Latin root meaning sand. Arenaviruses can be divided into two serogroups, which differ genetically and by geographical distribution: - LCMV-Lassa virus (Old World) complex: Ippy virus Lassa virus Lymphocytic choriomeningitis virus Mobala virus Mopeia virus - Ippy virus - Lassa virus - Lymphocytic choriomeningitis virus - Mobala virus - Mopeia virus - Tacaribe virus (New World) complex: Amapari virus Flexal virus Guanarito virus Junin virus Latino virus Machupo virus Oliveros virus Paraná virus Pichinde virus Pirital virus Sabiá virus Tacaribe virus Tamiami virus Whitewater Arroyo virus - Amapari virus - Flexal virus - Guanarito virus - Junin virus - Latino virus - Machupo virus - Oliveros virus - Paraná virus - Pichinde virus - Pirital virus - Sabiá virus - Tacaribe virus - Tamiami virus - Whitewater Arroyo virus Some arenaviruses are zoonotic pathogens and are generally associated with rodent-transmitted disease in humans. Each virus usually is associated with a particular rodent host species in which it is maintained. The virus particles are spherical and have an average diameter of 110-130 nanometers. All are enveloped in a lipid membrane. Viewed in cross-section, they show grainy particles that are ribosomes acquired from their host cells. It is this characteristic that gave them their name, derived from the Latin "arena," which means "sandy." Their genome, or genetic material, is composed of RNA only, and while their replication strategy is not completely understood, we know that new viral particles, called virions, are created by budding from the surface of their hosts’ cells. # External links - Detailed genomic and bioinformatic information about Arenaviridae at NIH-funded database. de:Arenaviridae nl:Arenavirussen Template:WS - ↑ "The Centers for Disease Control and Prevention"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}	https://www.wikidoc.org/index.php/Arenaviral_haemorrhagic_fever
7ecd4ca6ec331c8180fbd46014d6e53eccc5f4b4	wikidoc	Arfendazam	Arfendazam Arfendazam is a drug which is a benzodiazepine derivative. Arfendazam is a 1,5-benzodiazepine, with the nitrogen atoms located at positions 1 and 5 of the diazepine ring, and so is most closely related to other 1,5-benzodiazepines such as clobazam. Arfendazam has sedative and anxiolytic effects similar to those produced by other benzodiazepine derivatives, but is a partial agonist at GABAA receptors, so the sedative effects are relatively mild and it produces muscle relaxant effects only at very high doses. Arfendazam produces an active metabolite lofendazam, which is thought to be responsible for part of its effects.	Arfendazam Arfendazam is a drug which is a benzodiazepine derivative. Arfendazam is a 1,5-benzodiazepine, with the nitrogen atoms located at positions 1 and 5 of the diazepine ring, and so is most closely related to other 1,5-benzodiazepines such as clobazam. Arfendazam has sedative and anxiolytic effects similar to those produced by other benzodiazepine derivatives, but is a partial agonist at GABAA receptors, so the sedative effects are relatively mild and it produces muscle relaxant effects only at very high doses.[1][2] Arfendazam produces an active metabolite lofendazam, which is thought to be responsible for part of its effects.[3] Template:Pharma-stub	https://www.wikidoc.org/index.php/Arfendazam
85dce6e0c7a895ed0c23c91a3c8005e2572a0ddc	wikidoc	Exemestane	Exemestane # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Exemestane is an aromatase Inhibitor that is FDA approved for the treatment of advanced breast cancer in postmenopausal women and adjuvant treatment of postmenopausal women. Common adverse reactions include hot flushes, fatigue, arthralgia, headache, insomnia, and increased sweating, nausea, fatigue and increased appetite. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Exemestane is indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy. - Dosage: 25 mg tablet once daily after a meal. - Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. - Dosage: 25 mg tablet once daily after a meal. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Exemestane in adult patients. ### Non–Guideline-Supported Use - Prophylaxis of invasive breast cancer in postmenopausal women at increased risk. - Dosage: 25 mg/day for 5 years - Neoadjuvant treatment of postmenopausal women with breast cancer hormone-receptor positive. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness not established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Exemestane in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Exemestane in pediatric patients. # Contraindications - Exemestane tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients. - Exemestane may cause fetal harm when administered to a pregnant woman. Based on its mechanism of action exemestane is expected to result in adverse reproductive effects. In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient. - Exemestane is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. # Warnings Exemestane should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action. - In patients with early breast cancer, the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥1 was lower in the exemestane treatment group, compared with tamoxifen. - Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups. - Approximately 20% of patients receiving exemestane in clinical studies in advanced breast cancer experienced CTC grade 3 or 4 lymphocytopenia. Of these patients, 89% had a pre-existing lower grade lymphopenia. - Forty percent of patients either recovered or improved to a lesser severity while on treatment. - Patients did not have a significant increase in viral infections, and no opportunistic infections were observed. - Elevations of serum levels of AST, ALT, alkaline phosphatase, and gamma glutamyl transferase >5 times the upper value of the normal range (i.e., ≥ CTC grade 3) have been rarely reported in patients treated for advanced breast cancer but appear mostly attributable to the underlying presence of liver and/or bone metastases. - In the comparative study in advanced breast cancer patients, CTC grade 3 or 4 elevation of gamma glutamyl transferase without documented evidence of liver metastasis was reported in 2.7% of patients treated with exemestane and in 1.8% of patients treated with megestrol acetate. - In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving exemestane than either tamoxifen or placebo. - Treatment-emergent bilirubin elevations (any CTC grade) occurred in 5.3% of exemestane patients and 0.8% of tamoxifen patients on the Intergroup Exemestane Study (IES), and in 6.9% of exemestane treated patients vs. 0% of placebo treated patients in the 027 study. - CTC grade 3–4 increases in bilirubin occurred in 0.9% of exemestane treated patients compared to 0.1% of tamoxifen treated patients. - Alkaline phosphatase elevations of any CTC grade occurred in 15.0% of exemestane treated patients on the IES compared to 2.6% of tamoxifen treated patients, and in 13.7% of exemestane treated patients compared to 6.9% of placebo treated patients in study 027. - Creatinine elevations occurred in 5.8% of exemestane treated patients and 4.3% of tamoxifen treated patients on the IES and in 5.5% of exemestane treated patients and 0% of placebo treated patients in study 027. Reductions in bone mineral density (BMD) over time are seen with exemestane use. Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of bisphosphonates, vitamin D supplementation, and calcium was not allowed. During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment. Monitor patients for bone mineral density loss and treat as appropriate. Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be performed, due to the high prevalence of vitamin D deficiency in women with early breast cancer (EBC). Women with vitamin D deficiency should receive supplementation with vitamin D. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - The data described below reflect exposure to exemestane in 2325 postmenopausal women with early breast cancer. - Exemestane tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (14.1) and the 027 study (a randomized, placebo-controlled, double-blind, parallel group study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids, and coagulation factors over 2 years of treatment). - The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving exemestane or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving exemestane or placebo within the 027 study. Median duration of observation after randomization for exemestane was 34.5 months and for tamoxifen was 34.6 months. Median duration of observation was 30 months for both groups in the 027 study. - Certain adverse events, which were expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included myocardial infarction, other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic fractures, other primary cancer, and hospitalizations. - Exemestane was generally well tolerated and adverse events were usually mild to moderate. Within the IES study, discontinuations due to adverse events occurred in 6.3% and 5.1% of patients receiving exemestane and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo respectively within study 027. - Deaths due to any cause were reported for 1.3% of the exemestane treated patients and 1.4% of the tamoxifen treated patients within the IES study. There were 6 deaths due to stroke on the exemestane arm compared to 2 on tamoxifen. There were 5 deaths due to cardiac failure on the exemestane arm compared to 2 on tamoxifen. - The incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) was 1.6% in exemestane treated patients and 0.6% in tamoxifen treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated patients and 0.3% of tamoxifen treated patients. - Treatment-emergent adverse events and illnesses including all causalities and occurring with an incidence of ≥5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 2. - In the IES study, as compared to tamoxifen, exemestane was associated with a higher incidence of events in musculoskeletal disorders and in nervous system disorders, including the following events occurring with frequency lower than 5% (osteoporosis , osteochondrosis and trigger finger , paresthesia , carpal tunnel syndrome , and neuropathy ). - Diarrhea was also more frequent in the exemestane group (4.2% vs. 2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%). - After a median duration of therapy of about 30 months and a median follow-up of about 52 months, gastric ulcer was observed at a slightly higher frequency in the exemestane group compared to tamoxifen (0.7% vs. <0.1%). - The majority of patients on exemestane with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history. - Tamoxifen was associated with a higher incidence of muscle cramps , thromboembolism , endometrial hyperplasia , and uterine polyps . - A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. - Only one death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. - In the clinical trials program, only 3% of the patients discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations because of adverse events were uncommon (0.3%). - In the comparative study, adverse reactions were assessed for 358 patients treated with exemestane and 400 patients treated with megestrol acetate. Fewer patients receiving exemestane discontinued treatment because of adverse events than those treated with megestrol acetate (2% vs. 5%). Adverse events that were considered drug related or of indeterminate cause included hot flashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane and megestrol acetate, respectively. - The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17% vs. 8%). Table 4 shows the adverse events of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with exemestane or megestrol acetate. - Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative study for patients receiving exemestane 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema. - Additional adverse events of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), asthenia (6%), and fever (5%). - Adverse events of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis, rhinitis, and alopecia. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of exemestane. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Immune system disorders: hypersensitivity - Hepatobiliary disorders: hepatitis including cholestatic hepatitis - Nervous system disorders: paresthesia - Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis, urticaria, pruritus # Drug Interactions Drugs That Induce CYP 3A4 - Co-medications that induce CYP 3A4 (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, or St John's wort) may significantly decrease exposure to exemestane. - Dose modification is recommended for patients who are also receiving a strong CYP 3A4 inducer # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Exemestane can cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. exemestane is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies of exemestane in pregnant women. In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient. Radioactivity related to 14C-exemestane crossed the placenta of rats following oral administration of 1 mg/kg exemestane. The concentration of exemestane and its metabolites was approximately equivalent in maternal and fetal blood. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m2 basis). Prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day. Increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were also observed at these doses. No malformations were noted when exemestane was administered to pregnant rats during the organogenesis period at doses up to 810 mg/kg/day (approximately 320 times the recommended human dose on a mg/m2 basis). Daily doses of exemestane, given to rabbits during organogenesis, caused a decrease in placental weight at 90 mg/kg/day (approximately 70 times the recommended human daily dose on a mg/m2 basis). Abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. There was no increase in the incidence of malformations in rabbits at doses up to 270 mg/kg/day (approximately 210 times the recommended human dose on a mg/m2 basis). If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Pregnancy Category (AUS): C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Exemestane in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Exemestane during labor and delivery. ### Nursing Mothers Exemestane is only indicated in postmenopausal women. However, radioactivity related to exemestane appeared in rat milk within 15 minutes of oral administration of radiolabeled exemestane. Concentrations of exemestane and its metabolites were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral dose of 1 mg/kg 14C-exemestane. It is not known whether exemestane is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reaction in nursing infants from exemestane, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range. ### Gender The pharmacokinetics of exemestane following administration of a single, 25-mg tablet to fasted healthy males (mean age 32 years) were similar to the pharmacokinetics of exemestane in fasted healthy postmenopausal women (mean age 55 years). ### Race The influence of race on exemestane pharmacokinetics has not been evaluated. ### Renal Impairment The AUC of exemestane was increased in subjects with moderate or severe renal impairment (creatinine clearance <35 mL/min/1.73 m2). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life- threatening adverse events, dosage adjustment does not appear to be necessary. ### Hepatic Impairment The AUC of exemestane was increased in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life-threatening adverse events, dosage adjustment does not appear to be necessary. ### Females of Reproductive Potential and Males In a pilot reproductive study in rats, male rats were treated with doses of 125–1000 mg/kg/day exemestane, beginning 63 days prior to and during cohabitation. Untreated female rats showed reduced fertility when mated to males treated with ≥500 mg/kg/day exemestane (≥200 times the recommended human dose on a mg/m2 basis). In a separate study, exemestane was given to female rats at 4–100 mg/kg/day beginning 14 days prior to mating and through day 15 or 20 of gestation. Exemestane increased the placental weights at ≥4 mg/kg/day (≥1.5 times the human dose on a mg/m2 basis). Exemestane showed no effects on ovarian function, mating behavior, and conception rate in rats given doses up to 20 mg/kg/day (approximately 8 times the recommended human dose on a mg/m2 basis); however, decreases in mean litter size and fetal body weight, along with delayed ossification were evidenced at ≥20 mg/kg/day. In general toxicology studies, changes in the ovary, including hyperplasia, an increase in the incidence of ovarian cysts, and a decrease in corpora lutea were observed with variable frequency in mice, rats, and dogs at doses that ranged from 3–20 times the human dose on a mg/m2 basis. ### Immunocompromised Patients There is no FDA guidance one the use of Exemestane in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Exemestane Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Exemestane and IV administrations. # Overdosage Clinical trials have been conducted with exemestane given as a single dose to healthy female volunteers at doses as high as 800 mg and daily for 12 weeks to postmenopausal women with advanced breast cancer at doses as high as 600 mg. These dosages were well tolerated. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated. A male child (age unknown) accidentally ingested a 25-mg tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leucocytosis (WBC 25000/mm3 with 90% neutrophils). Blood tests were repeated 4 days after the incident and were normal. No treatment was given. In mice, mortality was observed after a single oral dose of exemestane of 3200 mg/kg, the lowest dose tested (about 640 times the recommended human dose on a mg/m2 basis). In rats and dogs, mortality was observed after single oral doses of exemestane of 5000 mg/kg (about 2000 times the recommended human dose on a mg/m2 basis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/m2 basis), respectively. Convulsions were observed after single doses of exemestane of 400 mg/kg and 3000 mg/kg in mice and dogs (approximately 80 and 4000 times the recommended human dose on a mg/m2 basis), respectively. # Pharmacology ## Mechanism of Action Breast cancer cell growth may be estrogen-dependent. Aromatase is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme, causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme. ## Structure Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structural formula is as follows: ## Pharmacodynamics Multiple doses of exemestane ranging from 0.5 to 600 mg/day were administered to postmenopausal women with advanced breast cancer. Plasma estrogen (estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5-mg daily dose of exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose. Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to 3 days after dosing and persisted for 4 to 5 days. In multiple-dose trials of doses up to 200 mg daily, exemestane selectivity was assessed by examining its effect on adrenal steroids. Exemestane did not affect cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane treatment. Exemestane does not bind significantly to steroidal receptors, except for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100 times that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on circulating levels of androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, and were associated with small decreases in circulating levels of testosterone. Increases in testosterone and androstenedione levels have been observed at daily doses of 200 mg or more. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight, nondose-dependent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level. Exemestane 25 mg daily had no significant effect on thyroid function . In study 027 of postmenopausal women with early breast cancer treated with exemestane (N=73) or placebo (N=73), there was no change in the coagulation parameters activated partial thromboplastin time , prothrombin time , and fibrinogen. Plasma HDL cholesterol was decreased 6–9% in exemestane treated patients; total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was also observed in exemestane treated patients compared with a 12% increase seen with placebo. ## Pharmacokinetics Following oral administration to healthy postmenopausal women, plasma concentrations of exemestane decline polyexponentially with a mean terminal half-life of about 24 hours. The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose. Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng∙h/mL) were about twice those in healthy women (41.4 ng∙h/mL). Following oral administration, exemestane appeared to be absorbed more rapidly in women with breast cancer than in the healthy women, with a mean -tmax of 1.2 hours in the women with breast cancer and 2.9 hours in healthy women. Approximately 42% of radiolabeled exemestane was absorbed from the gastrointestinal tract. A high-fat breakfast increased AUC and Cmax of exemestane by 59% and 39%, respectively, compared to fasted state. Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α11-acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible. Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity. Studies using human liver preparations indicate that cytochrome P 450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Exemestane is metabolized also by aldoketoreductases. Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose. ## Nonclinical Toxicology A 2-year carcinogenicity study in mice at doses of 50, 150, and 450 mg/kg/day exemestane (gavage), resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both genders at the high dose level. Plasma AUC (0–24hr) at the high dose were 2575 ± 386 and 5667 ± 1833 ng.hr/mL in males and females (approx. 34 and 75 fold the AUC in postmenopausal patients at the recommended clinical dose). An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day. Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown. A separate carcinogenicity study was conducted in rats at the doses of 30, 100, and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC(0–24hr) levels in male (1418 ± 287 ng.hr/mL) and female (2318 ± 1067 ng.hr/mL) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients receiving the recommended clinical dose. Exemestane was not mutagenic in vitro in bacteria (Ames test) or mammalian cells (V79 Chinese hamster lung cells). Exemestane was clastogenic in human lymphocytes in vitro without metabolic activation but was not clastogenic in vivo (micronucleus assay in mouse bone marrow). Exemestane did not increase unscheduled DNA synthesis in rat hepatocytes when tested in vitro. # Clinical Studies The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) vs. tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive an additional 3 or 2 years of exemestane or tamoxifen to complete a total of 5 years of hormonal therapy. The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to exemestane rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause. The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated. A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to exemestane (exemestane tablets) 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 5. Prior breast cancer therapy is summarized in Table 6. After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the exemestane group and 307 in the tamoxifen group. Disease-free survival in the intent-to-treat population was statistically significantly improved in the exemestane arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the exemestane arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy. Overall survival was not significantly different in the two groups, with 116 deaths occurring in the exemestane group and 137 in the tamoxifen group. Exemestane 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease. The primary purpose of the three studies was evaluation of objective response rate (complete response and partial response ). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive exemestane (exemestane tablets) 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 9. The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that exemestane was not different from megestrol acetate. Response rates for exemestane from the two single-arm trials were 23.4% and 28.1%. There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2. # How Supplied - Exemestane 25 mg tablets - 30 tablet bottle - NDC 0009-7663-04 ## Storage Store at 25°C (77ºF) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be advised that exemestane is not for use in premenopausal women. Patients should be informed that they should not take estrogen-containing agents while they are taking exemestane as these could interfere with its pharmacologic action. Patients should be informed that exemestane lowers the level of estrogen in the body. This may lead to reduction in bone mineral density (BMD) over time. The lower the BMD, the greater the risk of osteoporosis and fracture. # Precautions with Alcohol Alcohol-Exemestane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Aromasin # Look-Alike Drug Names There is limited information regarding Exemestane Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Exemestane Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]; Sree Teja Yelamanchili, MBBS [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Exemestane is an aromatase Inhibitor that is FDA approved for the treatment of advanced breast cancer in postmenopausal women and adjuvant treatment of postmenopausal women. Common adverse reactions include hot flushes, fatigue, arthralgia, headache, insomnia, and increased sweating, nausea, fatigue and increased appetite. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Exemestane is indicated for adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy. - Dosage: 25 mg tablet once daily after a meal. - Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. - Dosage: 25 mg tablet once daily after a meal. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Exemestane in adult patients. ### Non–Guideline-Supported Use - Prophylaxis of invasive breast cancer in postmenopausal women at increased risk. - Dosage: 25 mg/day for 5 years [1] - Neoadjuvant treatment of postmenopausal women with breast cancer hormone-receptor positive. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness not established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Exemestane in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Exemestane in pediatric patients. # Contraindications - Exemestane tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of the excipients. - Exemestane may cause fetal harm when administered to a pregnant woman. Based on its mechanism of action exemestane is expected to result in adverse reproductive effects. In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient. - Exemestane is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. # Warnings Exemestane should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action. - In patients with early breast cancer, the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥1 was lower in the exemestane treatment group, compared with tamoxifen. - Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups. - Approximately 20% of patients receiving exemestane in clinical studies in advanced breast cancer experienced CTC grade 3 or 4 lymphocytopenia. Of these patients, 89% had a pre-existing lower grade lymphopenia. - Forty percent of patients either recovered or improved to a lesser severity while on treatment. - Patients did not have a significant increase in viral infections, and no opportunistic infections were observed. - Elevations of serum levels of AST, ALT, alkaline phosphatase, and gamma glutamyl transferase >5 times the upper value of the normal range (i.e., ≥ CTC grade 3) have been rarely reported in patients treated for advanced breast cancer but appear mostly attributable to the underlying presence of liver and/or bone metastases. - In the comparative study in advanced breast cancer patients, CTC grade 3 or 4 elevation of gamma glutamyl transferase without documented evidence of liver metastasis was reported in 2.7% of patients treated with exemestane and in 1.8% of patients treated with megestrol acetate. - In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving exemestane than either tamoxifen or placebo. - Treatment-emergent bilirubin elevations (any CTC grade) occurred in 5.3% of exemestane patients and 0.8% of tamoxifen patients on the Intergroup Exemestane Study (IES), and in 6.9% of exemestane treated patients vs. 0% of placebo treated patients in the 027 study. - CTC grade 3–4 increases in bilirubin occurred in 0.9% of exemestane treated patients compared to 0.1% of tamoxifen treated patients. - Alkaline phosphatase elevations of any CTC grade occurred in 15.0% of exemestane treated patients on the IES compared to 2.6% of tamoxifen treated patients, and in 13.7% of exemestane treated patients compared to 6.9% of placebo treated patients in study 027. - Creatinine elevations occurred in 5.8% of exemestane treated patients and 4.3% of tamoxifen treated patients on the IES and in 5.5% of exemestane treated patients and 0% of placebo treated patients in study 027. Reductions in bone mineral density (BMD) over time are seen with exemestane use. Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of bisphosphonates, vitamin D supplementation, and calcium was not allowed. During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment. Monitor patients for bone mineral density loss and treat as appropriate. Routine assessment of 25-hydroxy vitamin D levels prior to the start of aromatase inhibitor treatment should be performed, due to the high prevalence of vitamin D deficiency in women with early breast cancer (EBC). Women with vitamin D deficiency should receive supplementation with vitamin D. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - The data described below reflect exposure to exemestane in 2325 postmenopausal women with early breast cancer. - Exemestane tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (14.1) and the 027 study (a randomized, placebo-controlled, double-blind, parallel group study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids, and coagulation factors over 2 years of treatment). - The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving exemestane or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving exemestane or placebo within the 027 study. Median duration of observation after randomization for exemestane was 34.5 months and for tamoxifen was 34.6 months. Median duration of observation was 30 months for both groups in the 027 study. - Certain adverse events, which were expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included myocardial infarction, other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic fractures, other primary cancer, and hospitalizations. - Exemestane was generally well tolerated and adverse events were usually mild to moderate. Within the IES study, discontinuations due to adverse events occurred in 6.3% and 5.1% of patients receiving exemestane and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo respectively within study 027. - Deaths due to any cause were reported for 1.3% of the exemestane treated patients and 1.4% of the tamoxifen treated patients within the IES study. There were 6 deaths due to stroke on the exemestane arm compared to 2 on tamoxifen. There were 5 deaths due to cardiac failure on the exemestane arm compared to 2 on tamoxifen. - The incidence of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) was 1.6% in exemestane treated patients and 0.6% in tamoxifen treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated patients and 0.3% of tamoxifen treated patients. - Treatment-emergent adverse events and illnesses including all causalities and occurring with an incidence of ≥5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 2. - In the IES study, as compared to tamoxifen, exemestane was associated with a higher incidence of events in musculoskeletal disorders and in nervous system disorders, including the following events occurring with frequency lower than 5% (osteoporosis [4.6% vs. 2.8%], osteochondrosis and trigger finger [0.3% vs. 0 for both events], paresthesia [2.6% vs. 0.9%], carpal tunnel syndrome [2.4% vs. 0.2%], and neuropathy [0.6% vs. 0.1%]). - Diarrhea was also more frequent in the exemestane group (4.2% vs. 2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%). - After a median duration of therapy of about 30 months and a median follow-up of about 52 months, gastric ulcer was observed at a slightly higher frequency in the exemestane group compared to tamoxifen (0.7% vs. <0.1%). - The majority of patients on exemestane with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history. - Tamoxifen was associated with a higher incidence of muscle cramps [3.1% vs. 1.5%], thromboembolism [2.0% vs. 0.9%], endometrial hyperplasia [1.7% vs. 0.6%], and uterine polyps [2.4% vs. 0.4%]. - A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. - Only one death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. - In the clinical trials program, only 3% of the patients discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations because of adverse events were uncommon (0.3%). - In the comparative study, adverse reactions were assessed for 358 patients treated with exemestane and 400 patients treated with megestrol acetate. Fewer patients receiving exemestane discontinued treatment because of adverse events than those treated with megestrol acetate (2% vs. 5%). Adverse events that were considered drug related or of indeterminate cause included hot flashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane and megestrol acetate, respectively. - The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17% vs. 8%). Table 4 shows the adverse events of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with exemestane or megestrol acetate. - Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative study for patients receiving exemestane 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema. - Additional adverse events of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), asthenia (6%), and fever (5%). - Adverse events of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis, rhinitis, and alopecia. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of exemestane. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Immune system disorders: hypersensitivity - Hepatobiliary disorders: hepatitis including cholestatic hepatitis - Nervous system disorders: paresthesia - Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis, urticaria, pruritus # Drug Interactions Drugs That Induce CYP 3A4 - Co-medications that induce CYP 3A4 (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, or St John's wort) may significantly decrease exposure to exemestane. - Dose modification is recommended for patients who are also receiving a strong CYP 3A4 inducer # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X Exemestane can cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. exemestane is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies of exemestane in pregnant women. In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient. Radioactivity related to 14C-exemestane crossed the placenta of rats following oral administration of 1 mg/kg exemestane. The concentration of exemestane and its metabolites was approximately equivalent in maternal and fetal blood. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m2 basis). Prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day. Increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were also observed at these doses. No malformations were noted when exemestane was administered to pregnant rats during the organogenesis period at doses up to 810 mg/kg/day (approximately 320 times the recommended human dose on a mg/m2 basis). Daily doses of exemestane, given to rabbits during organogenesis, caused a decrease in placental weight at 90 mg/kg/day (approximately 70 times the recommended human daily dose on a mg/m2 basis). Abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. There was no increase in the incidence of malformations in rabbits at doses up to 270 mg/kg/day (approximately 210 times the recommended human dose on a mg/m2 basis). If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Pregnancy Category (AUS): C There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Exemestane in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Exemestane during labor and delivery. ### Nursing Mothers Exemestane is only indicated in postmenopausal women. However, radioactivity related to exemestane appeared in rat milk within 15 minutes of oral administration of radiolabeled exemestane. Concentrations of exemestane and its metabolites were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral dose of 1 mg/kg 14C-exemestane. It is not known whether exemestane is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reaction in nursing infants from exemestane, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range. ### Gender The pharmacokinetics of exemestane following administration of a single, 25-mg tablet to fasted healthy males (mean age 32 years) were similar to the pharmacokinetics of exemestane in fasted healthy postmenopausal women (mean age 55 years). ### Race The influence of race on exemestane pharmacokinetics has not been evaluated. ### Renal Impairment The AUC of exemestane was increased in subjects with moderate or severe renal impairment (creatinine clearance <35 mL/min/1.73 m2). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life- threatening adverse events, dosage adjustment does not appear to be necessary. ### Hepatic Impairment The AUC of exemestane was increased in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life-threatening adverse events, dosage adjustment does not appear to be necessary. ### Females of Reproductive Potential and Males In a pilot reproductive study in rats, male rats were treated with doses of 125–1000 mg/kg/day exemestane, beginning 63 days prior to and during cohabitation. Untreated female rats showed reduced fertility when mated to males treated with ≥500 mg/kg/day exemestane (≥200 times the recommended human dose on a mg/m2 basis). In a separate study, exemestane was given to female rats at 4–100 mg/kg/day beginning 14 days prior to mating and through day 15 or 20 of gestation. Exemestane increased the placental weights at ≥4 mg/kg/day (≥1.5 times the human dose on a mg/m2 basis). Exemestane showed no effects on ovarian function, mating behavior, and conception rate in rats given doses up to 20 mg/kg/day (approximately 8 times the recommended human dose on a mg/m2 basis); however, decreases in mean litter size and fetal body weight, along with delayed ossification were evidenced at ≥20 mg/kg/day. In general toxicology studies, changes in the ovary, including hyperplasia, an increase in the incidence of ovarian cysts, and a decrease in corpora lutea were observed with variable frequency in mice, rats, and dogs at doses that ranged from 3–20 times the human dose on a mg/m2 basis. ### Immunocompromised Patients There is no FDA guidance one the use of Exemestane in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Exemestane Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Exemestane and IV administrations. # Overdosage Clinical trials have been conducted with exemestane given as a single dose to healthy female volunteers at doses as high as 800 mg and daily for 12 weeks to postmenopausal women with advanced breast cancer at doses as high as 600 mg. These dosages were well tolerated. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated. A male child (age unknown) accidentally ingested a 25-mg tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leucocytosis (WBC 25000/mm3 with 90% neutrophils). Blood tests were repeated 4 days after the incident and were normal. No treatment was given. In mice, mortality was observed after a single oral dose of exemestane of 3200 mg/kg, the lowest dose tested (about 640 times the recommended human dose on a mg/m2 basis). In rats and dogs, mortality was observed after single oral doses of exemestane of 5000 mg/kg (about 2000 times the recommended human dose on a mg/m2 basis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/m2 basis), respectively. Convulsions were observed after single doses of exemestane of 400 mg/kg and 3000 mg/kg in mice and dogs (approximately 80 and 4000 times the recommended human dose on a mg/m2 basis), respectively. # Pharmacology ## Mechanism of Action Breast cancer cell growth may be estrogen-dependent. Aromatase is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme, causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme. ## Structure Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structural formula is as follows: [[\|thumb\|none\|500px]] ## Pharmacodynamics Multiple doses of exemestane ranging from 0.5 to 600 mg/day were administered to postmenopausal women with advanced breast cancer. Plasma estrogen (estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5-mg daily dose of exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose. Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to 3 days after dosing and persisted for 4 to 5 days. In multiple-dose trials of doses up to 200 mg daily, exemestane selectivity was assessed by examining its effect on adrenal steroids. Exemestane did not affect cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane treatment. Exemestane does not bind significantly to steroidal receptors, except for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100 times that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on circulating levels of androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, and were associated with small decreases in circulating levels of testosterone. Increases in testosterone and androstenedione levels have been observed at daily doses of 200 mg or more. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight, nondose-dependent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level. Exemestane 25 mg daily had no significant effect on thyroid function [free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)]. In study 027 of postmenopausal women with early breast cancer treated with exemestane (N=73) or placebo (N=73), there was no change in the coagulation parameters activated partial thromboplastin time [APTT], prothrombin time [PT], and fibrinogen. Plasma HDL cholesterol was decreased 6–9% in exemestane treated patients; total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was also observed in exemestane treated patients compared with a 12% increase seen with placebo. ## Pharmacokinetics Following oral administration to healthy postmenopausal women, plasma concentrations of exemestane decline polyexponentially with a mean terminal half-life of about 24 hours. The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose. Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng∙h/mL) were about twice those in healthy women (41.4 ng∙h/mL). Following oral administration, exemestane appeared to be absorbed more rapidly in women with breast cancer than in the healthy women, with a mean -tmax of 1.2 hours in the women with breast cancer and 2.9 hours in healthy women. Approximately 42% of radiolabeled exemestane was absorbed from the gastrointestinal tract. A high-fat breakfast increased AUC and Cmax of exemestane by 59% and 39%, respectively, compared to fasted state. Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α11-acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible. Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity. Studies using human liver preparations indicate that cytochrome P 450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Exemestane is metabolized also by aldoketoreductases. Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose. ## Nonclinical Toxicology A 2-year carcinogenicity study in mice at doses of 50, 150, and 450 mg/kg/day exemestane (gavage), resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both genders at the high dose level. Plasma AUC (0–24hr) at the high dose were 2575 ± 386 and 5667 ± 1833 ng.hr/mL in males and females (approx. 34 and 75 fold the AUC in postmenopausal patients at the recommended clinical dose). An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day. Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown. A separate carcinogenicity study was conducted in rats at the doses of 30, 100, and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC(0–24hr) levels in male (1418 ± 287 ng.hr/mL) and female (2318 ± 1067 ng.hr/mL) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients receiving the recommended clinical dose. Exemestane was not mutagenic in vitro in bacteria (Ames test) or mammalian cells (V79 Chinese hamster lung cells). Exemestane was clastogenic in human lymphocytes in vitro without metabolic activation but was not clastogenic in vivo (micronucleus assay in mouse bone marrow). Exemestane did not increase unscheduled DNA synthesis in rat hepatocytes when tested in vitro. # Clinical Studies The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) vs. tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive an additional 3 or 2 years of exemestane or tamoxifen to complete a total of 5 years of hormonal therapy. The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to exemestane rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause. The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated. A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to exemestane (exemestane tablets) 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 5. Prior breast cancer therapy is summarized in Table 6. After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the exemestane group and 307 in the tamoxifen group. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 8, Figure 1] in the exemestane arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the exemestane arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy. Overall survival was not significantly different in the two groups, with 116 deaths occurring in the exemestane group and 137 in the tamoxifen group. Exemestane 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease. The primary purpose of the three studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive exemestane (exemestane tablets) 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 9. The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that exemestane was not different from megestrol acetate. Response rates for exemestane from the two single-arm trials were 23.4% and 28.1%. There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2. # How Supplied - Exemestane 25 mg tablets - 30 tablet bottle - NDC 0009-7663-04 ## Storage Store at 25°C (77ºF) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be advised that exemestane is not for use in premenopausal women. Patients should be informed that they should not take estrogen-containing agents while they are taking exemestane as these could interfere with its pharmacologic action. Patients should be informed that exemestane lowers the level of estrogen in the body. This may lead to reduction in bone mineral density (BMD) over time. The lower the BMD, the greater the risk of osteoporosis and fracture. # Precautions with Alcohol Alcohol-Exemestane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Aromasin [2] # Look-Alike Drug Names There is limited information regarding Exemestane Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Aromasin
b77b254f242bad036e15c7bfa47fd1b58976dccc	wikidoc	Aron Brand	Aron Brand Aron Brand-Auraban (1910-1977), born in Ozorkow, Poland, was an Israeli pediatric cardiologist. He served as chairman of the Israel Medical Association in Jerusalem, Israel, and founded the Jerusalem Academy of Medicine. Brand grew up in Kolo, where he attended heder and the Jewish gymnasium. In 1925, his father Ze'ev, a fervent Zionist, sent him to Palestine to study at Gymnasia Herzliya in Tel Aviv. In 1928, he studied philosophy and Jewish studies in Berlin. In the summer of 1939, Brand returned to Poland and married Esther Malka (Mala) nee Auerbach, of Przedecz. By a stroke of luck, they left Poland the week before the Nazis invaded. At the time, Brand was a teacher at the Ma'aleh School in Jerusalem. The couple had three sons, Avraham, Natan and Haim. In 1955, Brand founded the Jerusalem Academy of Medicine. From 1964 until his death, he headed the Pediatric Department of Bikur Cholim Hospital in Jerusalem. He was the founder of the Israel Institute for Medical History. Brand published numerous articles on medicine, philosophy, literature and art, and organized hundreds of lectures and workshops open to the general public on health-related issues. In 1976, he was awarded the Henrietta Szold Prize for his contribution to public health.	Aron Brand Aron Brand-Auraban (1910-1977), born in Ozorkow, Poland, was an Israeli pediatric cardiologist. He served as chairman of the Israel Medical Association in Jerusalem, Israel, and founded the Jerusalem Academy of Medicine. Brand grew up in Kolo, where he attended heder and the Jewish gymnasium. In 1925, his father Ze'ev, a fervent Zionist, sent him to Palestine to study at Gymnasia Herzliya in Tel Aviv. In 1928, he studied philosophy and Jewish studies in Berlin. In the summer of 1939, Brand returned to Poland and married Esther Malka (Mala) nee Auerbach, of Przedecz. By a stroke of luck, they left Poland the week before the Nazis invaded. At the time, Brand was a teacher at the Ma'aleh School in Jerusalem. The couple had three sons, Avraham, Natan and Haim. In 1955, Brand founded the Jerusalem Academy of Medicine. From 1964 until his death, he headed the Pediatric Department of Bikur Cholim Hospital in Jerusalem. He was the founder of the Israel Institute for Medical History. Brand published numerous articles on medicine, philosophy, literature and art, and organized hundreds of lectures and workshops open to the general public on health-related issues. In 1976, he was awarded the Henrietta Szold Prize for his contribution to public health.[1]	https://www.wikidoc.org/index.php/Aron_Brand
b39fe73222bf926cfeb79576c770d3757711058a	wikidoc	Paroxetine	Paroxetine # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Paroxetine is an antidepressive agent that is FDA approved for the treatment of major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include palpitations, vasodilatation, diaphoresis, constipation, diarrhea, loss of appetite, nausea, xerostomia, asthenia, dizziness, headache, insomnia, somnolence, tremor, blurred vision, abnormal ejaculation, erectile dysfunction, orgasm disorder, reduced libido, yawning. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Paroxetine tablets, USP are indicated for the treatment of major depressive disorder. - The efficacy of paroxetine tablets in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder. A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least four of the following eight symptoms: Change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. - The effects of paroxetine tablets in hospitalized depressed patients have not been adequately studied. - The efficacy of paroxetine tablets in maintaining a response in major depressive disorder for up to one year was demonstrated in a placebo-controlled trial (see PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who elects to use paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. - Dosing Information - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least one week. - Maintenance Therapy: - There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. - Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for periods of up to one year with doses that averaged about 30 mg. - Paroxetine tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time consuming, or significantly interfere with social or occupational functioning. - The efficacy of paroxetine tablets was established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive compulsive disorder (see PHARMACOLOGY: Clinical Trials). - Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. - Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on placebo (see PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who elects to use paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see ADMINISTRATION). - Dosing Information - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least one week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day. - Maintenance Therapy: - Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. - Paroxetine tablets are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. - The efficacy of paroxetine tablets was established in three 10- to 12-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see PHARMACOLOGY: Clinical Trials). - Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. - Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (seeL PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who prescribes paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see ADMINISTRATION). - Dosing Information: - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least one week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day. - Maintenance Therapy: - Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. - Paroxetine tablets are indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. - The efficacy of paroxetine tablets was established in three 12-week trials in adult patients with social anxiety disorder (DSM-IV). Paroxetine tablets have not been studied in children or adolescents with social phobia (see PHARMACOLOGY: Clinical Trials). - The effectiveness of paroxetine tablets in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systematically evaluated in adequate and well controlled trials. Therefore, the physician who elects to prescribe paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see ADMINISTRATION). - Dosing Information - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of paroxetine tablets has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY: Clinical Trials). - Maintenance Therapy: - There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. ### Generalized Anxiety Disorder - Paroxetine tablets are indicated for the treatment of Generalized Anxiety Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. - The efficacy of paroxetine tablets in the treatment of GAD was established in two 8-week placebo-controlled trials in adults with GAD. Paroxetine tablets have not been studied in children or adolescents with Generalized Anxiety Disorder (see PHARMACOLOGY: Clinical Trials). - Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least three of the following six symptoms: Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. - The efficacy of paroxetine tablets in maintaining a response in patients with Generalized Anxiety Disorder, who responded during an 8-week acute treatment phase while taking paroxetine tablets and were then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-controlled trial (see PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who elects to use paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see ADMINISTRATION). - Dosing Information - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least one week. - Maintenance Therapy: - Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine tablets during an 8 week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. ### Posttraumatic stress disorder - Dosing Information - The recommended starting dose is 20 mg once daily and the established effective dose is 20 mg once daily. There is insufficient evidence to suggest that a higher dose would provide increased benefit. For patients who have an inadequate response, the dosage may be adjusted by increments of 10 mg daily at intervals of at least 1 week. ### Premenstrual dysphoric disorder - Dosing Information - Paroxetine controlled-release may be administered daily throughout the menstrual cycle or limited to daily administration during the luteal phase of the menstrual cycle. The usual initial dosage is 12.5 mg controlled-release as a single daily dose; the dose may be increased to 25 mg/day at intervals of at least 1 week. Doses of 12.5 mg/day and 25 mg/day have both been shown to be effective. - The effectiveness of paroxetine controlled-release for maintenance therapy beyond 3 menstrual cycles has not been evaluated; however, the continuation of treatment in a responding patient is reasonable due to the usual persistence of symptoms until menopause. Patients should be reassessed occasionally to determine the need for ongoing treatment. ### Social phobia - Dosing Information - For the immediate-release tablet, the usual initial dosage is 20 mg daily. For social anxiety disorder, additional benefit has not been shown for doses above 20 mg daily. Therefore, the recommended dosage is 20 mg daily . - For the controlled-release tablet, the usual initial dosage is 12.5 mg daily; the dose may be increased by increments of 12.5 mg/day at intervals of at least 1 week. Doses of 12.5 mg/day to 37.5 mg/day have been shown to be effective. The maximum recommended dose is 37.5 mg daily . - For maintenance therapy, the dose should be adjusted to the lowest effective dose and patients should be reassessed occasionally to determine the need for ongoing treatment. Long-term treatment is usually necessary because social anxiety disorder is a chronic condition . ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Fibromyalgia - FDA Approval: Adult, no; Pediatric, no - Efficacy: Adult, Evidence favors efficacy - Recommendation: Adult, Class IIb - Strength of Evidence: Adult, Category B # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Paroxetine FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Non–Guideline-Supported Use - Dosing Information - Safety and effectiveness of paroxetine have not been established in pediatric patients. # Contraindications - The use of MAOIs intended to treat psychiatric disorders with paroxetine tablets or within 14 days of stopping treatment with paroxetine tablets is contraindicated because of an increased risk of serotonin syndrome. The use of paroxetine tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). - Starting paroxetine tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and ADMINISTRATION). - Concomitant use with thioridazine is contraindicated. - Concomitant use in patients taking pimozide is contraindicated. - Paroxetine tablets are contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in paroxetine tablets. # Warnings Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. - If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS AND ADMINISTRATION: Discontinuation of Treatment with Paroxetine Tablets, for a description of the risks of discontinuation of paroxetine tablets). - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for paroxetine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that paroxetine hydrochloride is not approved for use in treating bipolar depression. Serotonin Syndrome - The development of a potentially life threatening serotonin syndrome has been reported with SNRIs and SSRIs, including paroxetine hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of paroxetine hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated. Paroxetine hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine hydrochloride. Paroxetine hydrochloride should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). - If concomitant use of paroxetine hydrochloride with certain other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. - Treatment with paroxetine hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Angle-Closure Glaucoma - The pupillary dilation that occurs following use of many antidepressant drugs including paroxetine hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Potential Interaction with Thioridazine - Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as Torsades de pointes-type arrhythmias, and sudden death. This effect appears to be dose related. - An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS). Usage in Pregnancy Teratogenic Effects - Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. The findings from these studies are summarized below: - A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery. - A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, nine had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8). - Two large case control studies using separate databases, each with > 9,000 birth defect cases and > 4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1 to 6, seven exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval, 1.3 to 8.8, six exposed infants). - Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations. - If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS: Discontinuation of Treatment with Paroxetine Hydrochloride). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options. Animal Findings - Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. Nonteratogenic Effects - Neonates exposed to paroxetine hydrochloride and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome). - Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including paroxetine hydrochloride) in pregnancy and PPHN. Other studies do not show a significant statistical association. - Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. - When treating a pregnant woman with paroxetine hydrochloride, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS: Post-Marketing Reports). ### Precautions General Activation of Mania/Hypomania - During premarketing testing, hypomania or mania occurred in approximately 1% of unipolar patients treated with paroxetine hydrochloride compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine hydrochloride and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine hydrochloride should be used cautiously in patients with a history of mania. Seizures - During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine hydrochloride, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine hydrochloride should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Discontinuation of Treatment with Paroxetine Hydrochloride - Recent clinical trials supporting the various approved indications for paroxetine hydrochloride employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for one week before treatment was stopped. - With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine hydrochloride and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self limiting and did not require medical intervention. - During marketing of paroxetine hydrochloride and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self limiting, there have been reports of serious discontinuation symptoms. - Patients should be monitored for these symptoms when discontinuing treatment with paroxetine hydrochloride. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). - See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of treatment with paroxetine hydrochloride in pediatric patients. Tamoxifen - Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions). However, other studies have failed to demonstrate such a risk. It is uncertain whether the coadministration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition. Akathisia - The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment. Hyponatremia - Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including paroxetine hydrochloride. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of paroxetine hydrochloride, should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. - Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Abnormal Bleeding - SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation. Bone Fracture - Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral density, should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling or bruising. Use in Patients with Concomitant Illness - Clinical experience with paroxetine hydrochloride in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine hydrochloride in patients with diseases or conditions that could affect metabolism or hemodynamic responses. - As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine hydrochloride. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine hydrochloride is prescribed for patients with narrow angle glaucoma. - Paroxetine hydrochloride has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine hydrochloride in double-blind, placebo-controlled trials, however, did not indicate that paroxetine hydrochloride is associated with the development of significant ECG abnormalities. Similarly, paroxetine hydrochloride does not cause any clinically important changes in heart rate or blood pressure. - Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance < 30 mL/min) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION). Information for Patients - Paroxetine tablets should not be chewed or crushed, and should be swallowed whole. - Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine hydrochloride and triptans, tramadol, or other serotonergic agents. - Patients should be advised that taking paroxetine hydrochloride can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide is available for paroxetine hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine hydrochloride. Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin and Warfarin) - Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Interference with Cognitive and Motor Performance - Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine hydrochloride has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine hydrochloride does not affect their ability to engage in such activities. Completing Course of Therapy - While patients may notice improvement with treatment with paroxetine hydrochloride in 1 to 4 weeks, they should be advised to continue therapy as directed. Concomitant Medication - Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol - Although paroxetine hydrochloride has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine hydrochloride. Pregnancy - Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic Effects and Nonteratogenic Effects). Nursing - Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS: Nursing Mothers). Laboratory Tests - There are no specific laboratory tests recommended. DRUG ABUSE AND DEPENDENCE Controlled Substance Class - Paroxetine hydrochloride is not a controlled substance. Physical and Psychologic Dependence - Paroxetine hydrochloride has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of paroxetine hydrochloride (e.g., development of tolerance, incrementations of dose, drug seeking behavior). # Adverse Reactions ## Clinical Trials Experience Associated With Discontinuation of Treatment - Twenty percent (1,199/6,145) of patients treated with paroxetine hydrochloride in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine hydrochloride in worldwide trials in social anxiety disorder, OCD, panic disorder, and GAD, respectively, discontinued treatment due to an adverse event. The most common events (≥ 1%) associated with discontinuation and considered to be drug-related (i.e., those events associated with dropout at a rate approximately twice or greater for paroxetine hydrochloride compared to placebo) included the following: Commonly Observed Adverse Events Major Depressive Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that for placebo, derived from Table 2) were: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. Obsessive Compulsive Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. Panic Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that for placebo, derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. Social Anxiety Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that for placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. Generalized Anxiety Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. Incidence in Controlled Clinical Trials - The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied. Major Depressive Disorder - Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6 week) placebo-controlled trials in which patients were dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder - Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine hydrochloride who participated in placebo-controlled trials of 12 weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine hydrochloride who participated in placebo-controlled trials of 10 to 12 weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine hydrochloride who participated in placebo-controlled trials of 12 weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day. Generalized Anxiety Disorder - Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on paroxetine hydrochloride who participated in placebo-controlled trials of 8 weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day. Dose Dependency of Adverse Events - A comparison of adverse event rates in a fixed-dose study comparing 10 mg, 20 mg, 30 mg, and 40 mg/day of paroxetine hydrochloride with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of paroxetine hydrochloride, as shown in the following table: - In a fixed-dose study comparing placebo and 20 mg, 40 mg, and 60 mg of paroxetine hydrochloride in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine hydrochloride to which patients were assigned. No new adverse events were observed in the group treated with 60 mg of paroxetine hydrochloride compared to any of the other treatment groups. - In a fixed-dose study comparing placebo and 10 mg, 20 mg, and 40 mg of paroxetine hydrochloride in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of paroxetine hydrochloride to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of paroxetine hydrochloride compared to any of the other treatment groups. - In a fixed-dose study comparing placebo and 20 mg, 40 mg, and 60 mg of paroxetine hydrochloride in the treatment of social anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine hydrochloride to which patients were assigned. - In a fixed-dose study comparing placebo and 20 mg and 40 mg of paroxetine hydrochloride in the treatment of generalized anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine hydrochloride to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation. Adaptation to Certain Adverse Events - Over a 4 to 6 week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence, and asthenia). Male and Female Sexual Dysfunction With SSRIs - Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. - Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence. - In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the reported incidence of sexual side effects in males and females with major depressive disorder, OCD, panic disorder, social anxiety disorder, and GAD are displayed in Table 6. - There are no adequate and well controlled studies examining sexual dysfunction with paroxetine treatment. - Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. - While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Weight and Vital Sign Changes - Significant weight loss may be an undesirable result of treatment with paroxetine hydrochloride for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss versus smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients treated with paroxetine hydrochloride in controlled clinical trials. ECG Changes - In an analysis of ECGs obtained in 682 patients treated with paroxetine hydrochloride and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group. Liver Function Tests - In placebo-controlled clinical trials, patients treated with paroxetine hydrochloride exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the paroxetine hydrochloride vs. placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities. Hallucinations - In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9,089 patients receiving drug and 4 of 3,187 patients receiving placebo. Other Events Observed During the Premarketing Evaluation of Paroxetine Hydrochloride - During its premarketing assessment in major depressive disorder, multiple doses of paroxetine hydrochloride were administered to 6,145 patients in phase two and three studies. The conditions and duration of exposure to paroxetine hydrochloride varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder, and generalized anxiety disorder, 542, 469, 522, and 735 patients, respectively, received multiple doses of paroxetine hydrochloride. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. - In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9,089 patients exposed to multiple doses of paroxetine hydrochloride who experienced an event of the type cited on at least one occasion while receiving paroxetine hydrochloride. All reported events are included except those already listed in Tables 2 to 4, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it. - Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are also described in the PRECAUTIONS section. - Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain; Rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer - Cardiovascular System: Frequent: Hypertension, tachycardia; Infrequent: Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; Rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles - Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; Rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries - Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis - Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; Rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia - Metabolic and Nutritional: Frequent: Weight gain; Infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; Rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased - Musculoskeletal System: Frequent: Arthralgia; Infrequent: Arthritis, arthrosis; Rare: Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany - Nervous System: Frequent: Emotional lability, vertigo; Infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; Rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome - Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; Rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration - Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; Rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash - Special Senses: Frequent: Tinnitus; Infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; Rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect - Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; Rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis ## Postmarketing Experience - Voluntary reports of adverse events in patients taking paroxetine hydrochloride that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson Syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including Torsades de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura), and premature births in pregnant women. There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine hydrochloride and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine hydrochloride was added to chronic metoprolol treatment. # Drug Interactions Tryptophan - As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine hydrochloride. Consequently, concomitant use of paroxetine hydrochloride with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome). Monoamine Oxidase Inhibitors - See CONTRAINDICATIONS and WARNINGS. Pimozide - In a controlled study of healthy volunteers, after paroxetine hydrochloride was titrated to 60 mg daily, coadministration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine hydrochloride is contraindicated (see CONTRAINDICATIONS). Serotonergic Drugs - Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride and the potential for serotonin syndrome, caution is advised when paroxetine hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol or St. John's Wort (see WARNINGS: Serotonin Syndrome). - The concomitant use of paroxetine hydrochloride with MAOIs (including linezolid and intravenous methylene blue) is contradicated (see CONTRADICATIONS). The concomitant use of paroxetine hydrochloride with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions: Tryptophan). Thioridazine - See CONTRAINDICATIONS and WARNINGS. Warfarin - Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine hydrochloride and warfarin should be undertaken with caution (see PRECAUTIONS: Information for Patients: Drugs That Interfere with Hemostasis). Triptans - There have been rare post-marketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine hydrochloride with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS: Serotonin Syndrome). Drugs Affecting Hepatic Metabolism - The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes. Cimetidine - Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where paroxetine hydrochloride (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine hydrochloride after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not studied. Phenobarbital - Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30 mg dose of paroxetine hydrochloride was administered at phenobarbital steady-state (100 mg once daily for 14 days), paroxetine AUC and T1/2 were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine hydrochloride exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the two drugs are both being chronically dosed. No initial dosage adjustment of paroxetine hydrochloride is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect. Phenytoin - When a single oral 30 mg dose of paroxetine hydrochloride was administered at phenytoin steady-state (300 mg once daily for 14 days), paroxetine AUC and T1/2 were reduced (by an average of 50% and 35%, respectively) compared to paroxetine hydrochloride administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady-state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the two drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Post-Marketing Reports). Drugs Metabolized by CYP2D6 - Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (> 90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine hydrochloride. In one study, daily dosing of paroxetine hydrochloride (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T1/2 by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In one study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady-state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady-state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. - Concomitant use of paroxetine hydrochloride with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine hydrochloride or the other drug. - Therefore, coadministration of paroxetine hydrochloride with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. - However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS). - Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS). - At steady-state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: Drug Interactions: Tricyclic Antidepressants (TCAs)). Drugs Metabolized by Cytochrome CYP3A4 - An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Tricyclic Antidepressants (TCAs) - Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine hydrochloride, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine hydrochloride (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6). Drugs Highly Bound to Plasma Protein - Because paroxetine is highly bound to plasma protein, administration of paroxetine hydrochloride to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs. Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin and Warfarin) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued. Alcohol - Although paroxetine hydrochloride does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine hydrochloride. Lithium - A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine hydrochloride and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine hydrochloride is coadministered with lithium. Digoxin - The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady-state. Mean digoxin AUC at steady-state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution. Diazepam - Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated. Procyclidine - Daily oral dosing of paroxetine tablets (30 mg once daily) increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady-state. If anticholinergic effects are seen, the dose of procyclidine should be reduced. Beta-Blockers - In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine hydrochloride (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Post-Marketing Reports). Theophylline - Reports of elevated theophylline levels associated with treatment with paroxetine hydrochloride have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered. Fosamprenavir/Ritonavir - Coadministration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy). Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of ECT and paroxetine hydrochloride. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Teratogenic Effects - Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. The findings from these studies are summarized below: - A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery. - A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, nine had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8). - Two large case control studies using separate databases, each with > 9,000 birth defect cases and > 4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1 to 6, seven exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval, 1.3 to 8.8, six exposed infants). - Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations. - If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS: Discontinuation of Treatment with Paroxetine Hydrochloride). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options. Animal Findings - Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. Nonteratogenic Effects - Neonates exposed to paroxetine hydrochloride and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome). - Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including paroxetine hydrochloride) in pregnancy and PPHN. Other studies do not show a significant statistical association. - Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. - When treating a pregnant woman with paroxetine hydrochloride, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see ADMINISTRATION and ADVERSE REACTIONS: Post-Marketing Reports). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Paroxetine in women who are pregnant. ### Labor and Delivery - The effect of paroxetine on labor and delivery in humans is unknown. ### Nursing Mothers - Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when paroxetine hydrochloride is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with immediate-release paroxetine hydrochloride, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine hydrochloride in a child or adolescent must balance the potential risks with the clinical need. Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as paroxetine tablets. - In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine hydrochloride and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. - Events reported upon discontinuation of treatment with paroxetine hydrochloride in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine hydrochloride and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see DOSAGE AND ADMINISTRATION: Discontinuation of Treatment with Paroxetine Tablets). ### Geriatic Use - SSRIs and SNRIs, including paroxetine hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS:Hyponatremia). - In worldwide premarketing clinical trials with paroxetine hydrochloride, 17% of patients treated with paroxetine hydrochloride (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). ### Gender - There is no FDA guidance on the use of Paroxetine with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Paroxetine with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Paroxetine in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Paroxetine in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Paroxetine in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Paroxetine in patients who are immunocompromised. # Administration and Monitoring ### Administration Major Depressive Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least one week. Maintenance Therapy - There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. - Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for periods of up to one year with doses that averaged about 30 mg. Obsessive Compulsive Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least one week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day. Maintenance Therapy - Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Panic Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The target dose of paroxetine tablets in the treatment of panic disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least one week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets. The maximum dosage should not exceed 60 mg/day. Maintenance Therapy - Long-term maintenance of efficacy was demonstrated in a 3 month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Social Anxiety Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of paroxetine tablets has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY: Clinical Trials). Maintenance Therapy - There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Generalized Anxiety Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least one week. Maintenance Therapy - Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine tablets during an 8 week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Special Populations Treatment of Pregnant Women During the Third Trimester - Neonates exposed to paroxetine tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or Hepatic Impairment - The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day. Switching a Patient to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with paroxetine tablets. Conversely, at least 14 days should be allowed after stopping paroxetine tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of Paroxetine Tablets with Other MAOIs Such as Linezolid or Methylene Blue - Do not start paroxetine tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). - In some cases, a patient already receiving therapy with paroxetine tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, paroxetine tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with paroxetine tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). - The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with paroxetine tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). Discontinuation of Treatment with Paroxetine Tablets - Symptoms associated with discontinuation of paroxetine tablets have been reported (see PRECAUTIONS: Discontinuation of Treatment with Paroxetine Hydrochloride). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine tablets is being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. ### Monitoring - There is limited information regarding Monitoring of Paroxetine in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Paroxetine in the drug label. # Overdosage Human Experience - Since the introduction of paroxetine hydrochloride in the United States, 342 spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or the presence of significant comorbid conditions. Of 145 nonfatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered. - Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including Torsades de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention. Overdosage Management - No specific antidotes for paroxetine are known. Treatment should consist of those general measures employed in the management of overdosage with any drugs effective in the treatment of major depressive disorder. - Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion or exchange transfusion are unlikely to be of benefit. - A specific caution involves patients who are taking or have recently taken paroxetine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see PRECAUTIONS: Drug Interactions: Drugs Metabolized by Cytochrome CYP2D6). - In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR). # Pharmacology ## Mechanism of Action ## Structure - Paroxetine hydrochloride is an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (3S-trans)-3--4-(4-fluorophenyl)-piperidine hydrochloride hemihydrate and has the molecular formula of C19H20FNO3HCl1/2H2O. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride is: - Paroxetine hydrochloride (hemihydrate), USP is an odorless, white or almost white crystalline powder, having a melting point range of 129° to 131°C and a solubility of 5.4 mg/mL in water. - Each film-coated tablet contains paroxetine hydrochloride hemihydrate equivalent to 10 mg, 20 mg, 30 mg or 40 mg paroxetine. Inactive ingredients consist of dibasic calcium phosphate dihydrate, FD&C Blue No. 1 Aluminum Lake, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, sodium starch glycolate, titanium dioxide and triacetin. - Paroxetine hydrochloride complies with USP Chromatographic Purity Test 1. ## Pharmacodynamics - The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and generalized anxiety disorder (GAD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic, and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. - Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially inactive. ## Pharmacokinetics - Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of paroxetine hydrochloride daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers). - In a meta analysis of paroxetine from four studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower Cmax or AUC than females. Absorption and Distribution - Paroxetine is equally bioavailable from the oral suspension and tablet. - Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady-state, mean values of Cmax, Tmax, Cmin, and T1/2were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21 hours (CV 32%), respectively. The steady-state Cmax and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that one of the enzymes that metabolizes paroxetine is readily saturable. - The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. - Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. - Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. Metabolism and Excretion - The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of paroxetine hydrochloride. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. - Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS: Drug Interactions: Drugs Metabolized by CYP2D6). - Approximately 64% of a 30 mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10 day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10 day post-dosing period. Other Clinical Pharmacology Information Specific Populations Renal and Liver Disease - Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min were approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, Cmax). - The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE AND ADMINISTRATION). Elderly Patients - In a multiple-dose study in the elderly at daily paroxetine doses of 20 mg, 30 mg, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND ADMINISTRATION). Drug-Drug Interactions - In vitro drug interaction studies reveal that paroxetine inhibits CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine (see PRECAUTIONS: Drug Interactions). Clinical Trials Major Depressive Disorder - The efficacy of paroxetine hydrochloride as a treatment for major depressive disorder has been established in six placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, paroxetine hydrochloride was shown to be significantly more effective than placebo in treating major depressive disorder by at least two of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine hydrochloride was significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. - A study of outpatients with major depressive disorder who had responded to paroxetine hydrochloride (HDRS total score <8) during an initial 8-week open-treatment phase and were then randomized to continuation on paroxetine hydrochloride or placebo for one year demonstrated a significantly lower relapse rate for patients taking paroxetine hydrochloride (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients. Obsessive Compulsive Disorder - The effectiveness of paroxetine hydrochloride in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients were treated with fixed doses of 20 mg, 40 mg, or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40 mg and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40 mg and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing paroxetine (20 mg to 60 mg daily) with clomipramine (25 mg to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. - The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1. - Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. - The long-term maintenance effects of paroxetine hydrochloride in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. Panic Disorder - The effectiveness of paroxetine hydrochloride in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1 to 3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine hydrochloride was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. - Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients. - Study 2 was a 12-week flexible-dose study comparing paroxetine (10 mg to 60 mg daily) and placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients. - Study 3 was a 12-week flexible-dose study comparing paroxetine (10 mg to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients. - In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine. - Long-term maintenance effects of paroxetine hydrochloride in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. - Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. Social Anxiety Disorder - The effectiveness of paroxetine hydrochloride in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of paroxetine hydrochloride compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS). - Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients, respectively. - Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day. - Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender. Generalized Anxiety Disorder - The effectiveness of paroxetine hydrochloride in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV). - Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine hydrochloride were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose. - Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine hydrochloride demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of paroxetine hydrochloride over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. - Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. - In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of paroxetine hydrochloride, were randomized to continuation of paroxetine hydrochloride at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of ≥ 2 points compared to baseline on the CGI-Severity of Illness scale, to a score of ≤ 3. Relapse during the double-blind phase was defined as an increase of ≥ 2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥ 4, or withdrawal due to lack of efficacy. Patients receiving continued paroxetine hydrochloride experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Two year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, and GAD on a mg/m2 basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg vs. 60 mg), the doses used in these carcinogenicity studies were only 2 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. Mutagenesis - Paroxetine produced no genotoxic effects in a battery of five in vitro and two in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats. Impairment of Fertility - Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men. - A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD or 2.4 times the MRHD for OCD on a mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2 basis). # Clinical Studies - There is limited information regarding Clinical Studies of Paroxetine in the drug label. # How Supplied - Paroxetine Tablets, USP are available as 10 mg, 20 mg, 30 mg and 40 mg tablets. - The 10 mg tablet is a blue film-coated, modified capsule-shaped, scored tablet debossed with M on one side of the tablet and N to the left of the score and 1 to the right of the score on the other side. They are available as follows: - NDC 0378-7001-93 - bottles of 30 tablets - NDC 0378-7001-10 - bottles of 1000 tablets - The 20 mg tablet is a blue film-coated, modified capsule-shaped, scored tablet debossed with M on one side of the tablet and N to the left of the score and 2 to the right of the score on the other side. They are available as follows: - NDC 0378-7002-93 - bottles of 30 tablets - NDC 0378-7002-10 - bottles of 1000 tablets - The 30 mg tablet is a blue film-coated, round, unscored tablet debossed with M over N3 on one side of the tablet and blank on the other side. They are available as follows: - NDC 0378-7003-93 - bottles of 30 tablets - NDC 0378-7003-10 - bottles of 1000 tablets - The 40 mg tablet is a blue film-coated, round, unscored tablet debossed with M over N4 on one side of the tablet and blank on the other side. They are available as follows: - NDC 0378-7004-93 - bottles of 30 tablets - NDC 0378-7004-10 - bottles of 1000 tablets ## Storage - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Paroxetine tablets should not be chewed or crushed, and should be swallowed whole. - Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine hydrochloride and triptans, tramadol, or other serotonergic agents. - Patients should be advised that taking paroxetine hydrochloride can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide is available for paroxetine hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine hydrochloride. Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin and Warfarin) - Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Interference with Cognitive and Motor Performance - Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine hydrochloride has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine hydrochloride does not affect their ability to engage in such activities. Completing Course of Therapy - While patients may notice improvement with treatment with paroxetine hydrochloride in 1 to 4 weeks, they should be advised to continue therapy as directed. Concomitant Medication - Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol - Although paroxetine hydrochloride has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine hydrochloride. Pregnancy - Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic Effects and Nonteratogenic Effects). Nursing - Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS: Nursing Mothers). # Precautions with Alcohol - Alcohol-Paroxetine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Paxil, Paxil CR. # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Paroxetine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Paroxetine is an antidepressive agent that is FDA approved for the treatment of major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include palpitations, vasodilatation, diaphoresis, constipation, diarrhea, loss of appetite, nausea, xerostomia, asthenia, dizziness, headache, insomnia, somnolence, tremor, blurred vision, abnormal ejaculation, erectile dysfunction, orgasm disorder, reduced libido, yawning. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Paroxetine tablets, USP are indicated for the treatment of major depressive disorder. - The efficacy of paroxetine tablets in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder. A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least four of the following eight symptoms: Change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. - The effects of paroxetine tablets in hospitalized depressed patients have not been adequately studied. - The efficacy of paroxetine tablets in maintaining a response in major depressive disorder for up to one year was demonstrated in a placebo-controlled trial (see PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who elects to use paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. - Dosing Information - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least one week. - Maintenance Therapy: - There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. - Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for periods of up to one year with doses that averaged about 30 mg. - Paroxetine tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time consuming, or significantly interfere with social or occupational functioning. - The efficacy of paroxetine tablets was established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive compulsive disorder (see PHARMACOLOGY: Clinical Trials). - Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. - Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on placebo (see PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who elects to use paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see ADMINISTRATION). - Dosing Information - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least one week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day. - Maintenance Therapy: - Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. - Paroxetine tablets are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. - The efficacy of paroxetine tablets was established in three 10- to 12-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see PHARMACOLOGY: Clinical Trials). - Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. - Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (seeL PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who prescribes paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see ADMINISTRATION). - Dosing Information: - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least one week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day. - Maintenance Therapy: - Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. - Paroxetine tablets are indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. - The efficacy of paroxetine tablets was established in three 12-week trials in adult patients with social anxiety disorder (DSM-IV). Paroxetine tablets have not been studied in children or adolescents with social phobia (see PHARMACOLOGY: Clinical Trials). - The effectiveness of paroxetine tablets in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systematically evaluated in adequate and well controlled trials. Therefore, the physician who elects to prescribe paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see ADMINISTRATION). - Dosing Information - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of paroxetine tablets has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY: Clinical Trials). - Maintenance Therapy: - There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. ### Generalized Anxiety Disorder - Paroxetine tablets are indicated for the treatment of Generalized Anxiety Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. - The efficacy of paroxetine tablets in the treatment of GAD was established in two 8-week placebo-controlled trials in adults with GAD. Paroxetine tablets have not been studied in children or adolescents with Generalized Anxiety Disorder (see PHARMACOLOGY: Clinical Trials). - Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least three of the following six symptoms: Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. - The efficacy of paroxetine tablets in maintaining a response in patients with Generalized Anxiety Disorder, who responded during an 8-week acute treatment phase while taking paroxetine tablets and were then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-controlled trial (see PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who elects to use paroxetine tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see ADMINISTRATION). - Dosing Information - Usual Initial Dosage: - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least one week. - Maintenance Therapy: - Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine tablets during an 8 week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. ### Posttraumatic stress disorder - Dosing Information - The recommended starting dose is 20 mg once daily and the established effective dose is 20 mg once daily. There is insufficient evidence to suggest that a higher dose would provide increased benefit. For patients who have an inadequate response, the dosage may be adjusted by increments of 10 mg daily at intervals of at least 1 week. ### Premenstrual dysphoric disorder - Dosing Information - Paroxetine controlled-release may be administered daily throughout the menstrual cycle or limited to daily administration during the luteal phase of the menstrual cycle. The usual initial dosage is 12.5 mg controlled-release as a single daily dose; the dose may be increased to 25 mg/day at intervals of at least 1 week. Doses of 12.5 mg/day and 25 mg/day have both been shown to be effective. - The effectiveness of paroxetine controlled-release for maintenance therapy beyond 3 menstrual cycles has not been evaluated; however, the continuation of treatment in a responding patient is reasonable due to the usual persistence of symptoms until menopause. Patients should be reassessed occasionally to determine the need for ongoing treatment. ### Social phobia - Dosing Information - For the immediate-release tablet, the usual initial dosage is 20 mg daily. For social anxiety disorder, additional benefit has not been shown for doses above 20 mg daily. Therefore, the recommended dosage is 20 mg daily [3]. - For the controlled-release tablet, the usual initial dosage is 12.5 mg daily; the dose may be increased by increments of 12.5 mg/day at intervals of at least 1 week. Doses of 12.5 mg/day to 37.5 mg/day have been shown to be effective. The maximum recommended dose is 37.5 mg daily [4]. - For maintenance therapy, the dose should be adjusted to the lowest effective dose and patients should be reassessed occasionally to determine the need for ongoing treatment. Long-term treatment is usually necessary because social anxiety disorder is a chronic condition [3][4]. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Fibromyalgia - FDA Approval: Adult, no; Pediatric, no - Efficacy: Adult, Evidence favors efficacy - Recommendation: Adult, Class IIb - Strength of Evidence: Adult, Category B # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Paroxetine FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Non–Guideline-Supported Use - Dosing Information - Safety and effectiveness of paroxetine have not been established in pediatric patients. # Contraindications - The use of MAOIs intended to treat psychiatric disorders with paroxetine tablets or within 14 days of stopping treatment with paroxetine tablets is contraindicated because of an increased risk of serotonin syndrome. The use of paroxetine tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION). - Starting paroxetine tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and ADMINISTRATION). - Concomitant use with thioridazine is contraindicated. - Concomitant use in patients taking pimozide is contraindicated. - Paroxetine tablets are contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in paroxetine tablets. # Warnings Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. - If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS AND ADMINISTRATION: Discontinuation of Treatment with Paroxetine Tablets, for a description of the risks of discontinuation of paroxetine tablets). - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for paroxetine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that paroxetine hydrochloride is not approved for use in treating bipolar depression. Serotonin Syndrome - The development of a potentially life threatening serotonin syndrome has been reported with SNRIs and SSRIs, including paroxetine hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). - Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. - The concomitant use of paroxetine hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated. Paroxetine hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine hydrochloride. Paroxetine hydrochloride should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). - If concomitant use of paroxetine hydrochloride with certain other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. - Treatment with paroxetine hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Angle-Closure Glaucoma - The pupillary dilation that occurs following use of many antidepressant drugs including paroxetine hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Potential Interaction with Thioridazine - Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as Torsades de pointes-type arrhythmias, and sudden death. This effect appears to be dose related. - An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS). Usage in Pregnancy Teratogenic Effects - Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. The findings from these studies are summarized below: - A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery. - A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, nine had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8). - Two large case control studies using separate databases, each with > 9,000 birth defect cases and > 4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1 to 6, seven exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval, 1.3 to 8.8, six exposed infants). - Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations. - If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS: Discontinuation of Treatment with Paroxetine Hydrochloride). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options. Animal Findings - Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. Nonteratogenic Effects - Neonates exposed to paroxetine hydrochloride and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome). - Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including paroxetine hydrochloride) in pregnancy and PPHN. Other studies do not show a significant statistical association. - Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. - When treating a pregnant woman with paroxetine hydrochloride, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS: Post-Marketing Reports). ### Precautions General Activation of Mania/Hypomania - During premarketing testing, hypomania or mania occurred in approximately 1% of unipolar patients treated with paroxetine hydrochloride compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine hydrochloride and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine hydrochloride should be used cautiously in patients with a history of mania. Seizures - During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine hydrochloride, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine hydrochloride should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Discontinuation of Treatment with Paroxetine Hydrochloride - Recent clinical trials supporting the various approved indications for paroxetine hydrochloride employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for one week before treatment was stopped. - With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine hydrochloride and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self limiting and did not require medical intervention. - During marketing of paroxetine hydrochloride and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self limiting, there have been reports of serious discontinuation symptoms. - Patients should be monitored for these symptoms when discontinuing treatment with paroxetine hydrochloride. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION). - See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of treatment with paroxetine hydrochloride in pediatric patients. Tamoxifen - Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions). However, other studies have failed to demonstrate such a risk. It is uncertain whether the coadministration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition. Akathisia - The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment. Hyponatremia - Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including paroxetine hydrochloride. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of paroxetine hydrochloride, should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. - Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Abnormal Bleeding - SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation. Bone Fracture - Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral density, should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling or bruising. Use in Patients with Concomitant Illness - Clinical experience with paroxetine hydrochloride in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine hydrochloride in patients with diseases or conditions that could affect metabolism or hemodynamic responses. - As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine hydrochloride. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine hydrochloride is prescribed for patients with narrow angle glaucoma. - Paroxetine hydrochloride has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine hydrochloride in double-blind, placebo-controlled trials, however, did not indicate that paroxetine hydrochloride is associated with the development of significant ECG abnormalities. Similarly, paroxetine hydrochloride does not cause any clinically important changes in heart rate or blood pressure. - Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance < 30 mL/min) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION). Information for Patients - Paroxetine tablets should not be chewed or crushed, and should be swallowed whole. - Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine hydrochloride and triptans, tramadol, or other serotonergic agents. - Patients should be advised that taking paroxetine hydrochloride can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide is available for paroxetine hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine hydrochloride. Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin and Warfarin) - Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Interference with Cognitive and Motor Performance - Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine hydrochloride has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine hydrochloride does not affect their ability to engage in such activities. Completing Course of Therapy - While patients may notice improvement with treatment with paroxetine hydrochloride in 1 to 4 weeks, they should be advised to continue therapy as directed. Concomitant Medication - Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol - Although paroxetine hydrochloride has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine hydrochloride. Pregnancy - Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic Effects and Nonteratogenic Effects). Nursing - Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS: Nursing Mothers). Laboratory Tests - There are no specific laboratory tests recommended. DRUG ABUSE AND DEPENDENCE Controlled Substance Class - Paroxetine hydrochloride is not a controlled substance. Physical and Psychologic Dependence - Paroxetine hydrochloride has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of paroxetine hydrochloride (e.g., development of tolerance, incrementations of dose, drug seeking behavior). # Adverse Reactions ## Clinical Trials Experience Associated With Discontinuation of Treatment - Twenty percent (1,199/6,145) of patients treated with paroxetine hydrochloride in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine hydrochloride in worldwide trials in social anxiety disorder, OCD, panic disorder, and GAD, respectively, discontinued treatment due to an adverse event. The most common events (≥ 1%) associated with discontinuation and considered to be drug-related (i.e., those events associated with dropout at a rate approximately twice or greater for paroxetine hydrochloride compared to placebo) included the following: Commonly Observed Adverse Events Major Depressive Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that for placebo, derived from Table 2) were: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. Obsessive Compulsive Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. Panic Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that for placebo, derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. Social Anxiety Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that for placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. Generalized Anxiety Disorder - The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine hydrochloride at least twice that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. Incidence in Controlled Clinical Trials - The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied. Major Depressive Disorder - Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6 week) placebo-controlled trials in which patients were dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder - Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine hydrochloride who participated in placebo-controlled trials of 12 weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine hydrochloride who participated in placebo-controlled trials of 10 to 12 weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine hydrochloride who participated in placebo-controlled trials of 12 weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day. Generalized Anxiety Disorder - Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on paroxetine hydrochloride who participated in placebo-controlled trials of 8 weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day. Dose Dependency of Adverse Events - A comparison of adverse event rates in a fixed-dose study comparing 10 mg, 20 mg, 30 mg, and 40 mg/day of paroxetine hydrochloride with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of paroxetine hydrochloride, as shown in the following table: - In a fixed-dose study comparing placebo and 20 mg, 40 mg, and 60 mg of paroxetine hydrochloride in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine hydrochloride to which patients were assigned. No new adverse events were observed in the group treated with 60 mg of paroxetine hydrochloride compared to any of the other treatment groups. - In a fixed-dose study comparing placebo and 10 mg, 20 mg, and 40 mg of paroxetine hydrochloride in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of paroxetine hydrochloride to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of paroxetine hydrochloride compared to any of the other treatment groups. - In a fixed-dose study comparing placebo and 20 mg, 40 mg, and 60 mg of paroxetine hydrochloride in the treatment of social anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine hydrochloride to which patients were assigned. - In a fixed-dose study comparing placebo and 20 mg and 40 mg of paroxetine hydrochloride in the treatment of generalized anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine hydrochloride to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation. Adaptation to Certain Adverse Events - Over a 4 to 6 week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence, and asthenia). Male and Female Sexual Dysfunction With SSRIs - Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. - Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence. - In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the reported incidence of sexual side effects in males and females with major depressive disorder, OCD, panic disorder, social anxiety disorder, and GAD are displayed in Table 6. - There are no adequate and well controlled studies examining sexual dysfunction with paroxetine treatment. - Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. - While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Weight and Vital Sign Changes - Significant weight loss may be an undesirable result of treatment with paroxetine hydrochloride for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss versus smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients treated with paroxetine hydrochloride in controlled clinical trials. ECG Changes - In an analysis of ECGs obtained in 682 patients treated with paroxetine hydrochloride and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group. Liver Function Tests - In placebo-controlled clinical trials, patients treated with paroxetine hydrochloride exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the paroxetine hydrochloride vs. placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities. Hallucinations - In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9,089 patients receiving drug and 4 of 3,187 patients receiving placebo. Other Events Observed During the Premarketing Evaluation of Paroxetine Hydrochloride - During its premarketing assessment in major depressive disorder, multiple doses of paroxetine hydrochloride were administered to 6,145 patients in phase two and three studies. The conditions and duration of exposure to paroxetine hydrochloride varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder, and generalized anxiety disorder, 542, 469, 522, and 735 patients, respectively, received multiple doses of paroxetine hydrochloride. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. - In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9,089 patients exposed to multiple doses of paroxetine hydrochloride who experienced an event of the type cited on at least one occasion while receiving paroxetine hydrochloride. All reported events are included except those already listed in Tables 2 to 4, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it. - Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are also described in the PRECAUTIONS section. - Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain; Rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer - Cardiovascular System: Frequent: Hypertension, tachycardia; Infrequent: Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; Rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles - Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; Rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries - Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis - Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; Rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia - Metabolic and Nutritional: Frequent: Weight gain; Infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; Rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased - Musculoskeletal System: Frequent: Arthralgia; Infrequent: Arthritis, arthrosis; Rare: Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany - Nervous System: Frequent: Emotional lability, vertigo; Infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; Rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome - Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; Rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration - Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; Rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash - Special Senses: Frequent: Tinnitus; Infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; Rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect - Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; Rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis ## Postmarketing Experience - Voluntary reports of adverse events in patients taking paroxetine hydrochloride that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson Syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including Torsades de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura), and premature births in pregnant women. There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine hydrochloride and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine hydrochloride was added to chronic metoprolol treatment. # Drug Interactions Tryptophan - As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine hydrochloride. Consequently, concomitant use of paroxetine hydrochloride with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome). Monoamine Oxidase Inhibitors - See CONTRAINDICATIONS and WARNINGS. Pimozide - In a controlled study of healthy volunteers, after paroxetine hydrochloride was titrated to 60 mg daily, coadministration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine hydrochloride is contraindicated (see CONTRAINDICATIONS). Serotonergic Drugs - Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride and the potential for serotonin syndrome, caution is advised when paroxetine hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol or St. John's Wort (see WARNINGS: Serotonin Syndrome). - The concomitant use of paroxetine hydrochloride with MAOIs (including linezolid and intravenous methylene blue) is contradicated (see CONTRADICATIONS). The concomitant use of paroxetine hydrochloride with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions: Tryptophan). Thioridazine - See CONTRAINDICATIONS and WARNINGS. Warfarin - Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine hydrochloride and warfarin should be undertaken with caution (see PRECAUTIONS: Information for Patients: Drugs That Interfere with Hemostasis). Triptans - There have been rare post-marketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine hydrochloride with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS: Serotonin Syndrome). Drugs Affecting Hepatic Metabolism - The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes. Cimetidine - Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where paroxetine hydrochloride (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine hydrochloride after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not studied. Phenobarbital - Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30 mg dose of paroxetine hydrochloride was administered at phenobarbital steady-state (100 mg once daily for 14 days), paroxetine AUC and T1/2 were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine hydrochloride exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the two drugs are both being chronically dosed. No initial dosage adjustment of paroxetine hydrochloride is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect. Phenytoin - When a single oral 30 mg dose of paroxetine hydrochloride was administered at phenytoin steady-state (300 mg once daily for 14 days), paroxetine AUC and T1/2 were reduced (by an average of 50% and 35%, respectively) compared to paroxetine hydrochloride administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady-state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the two drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Post-Marketing Reports). Drugs Metabolized by CYP2D6 - Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (> 90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine hydrochloride. In one study, daily dosing of paroxetine hydrochloride (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T1/2 by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In one study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady-state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady-state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. - Concomitant use of paroxetine hydrochloride with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine hydrochloride or the other drug. - Therefore, coadministration of paroxetine hydrochloride with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. - However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS). - Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS). - At steady-state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: Drug Interactions: Tricyclic Antidepressants (TCAs)). Drugs Metabolized by Cytochrome CYP3A4 - An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Tricyclic Antidepressants (TCAs) - Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine hydrochloride, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine hydrochloride (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6). Drugs Highly Bound to Plasma Protein - Because paroxetine is highly bound to plasma protein, administration of paroxetine hydrochloride to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs. Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin and Warfarin) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued. Alcohol - Although paroxetine hydrochloride does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine hydrochloride. Lithium - A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine hydrochloride and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine hydrochloride is coadministered with lithium. Digoxin - The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady-state. Mean digoxin AUC at steady-state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution. Diazepam - Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated. Procyclidine - Daily oral dosing of paroxetine tablets (30 mg once daily) increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady-state. If anticholinergic effects are seen, the dose of procyclidine should be reduced. Beta-Blockers - In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine hydrochloride (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Post-Marketing Reports). Theophylline - Reports of elevated theophylline levels associated with treatment with paroxetine hydrochloride have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered. Fosamprenavir/Ritonavir - Coadministration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy). Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of ECT and paroxetine hydrochloride. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Teratogenic Effects - Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. The findings from these studies are summarized below: - A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery. - A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, nine had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8). - Two large case control studies using separate databases, each with > 9,000 birth defect cases and > 4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1 to 6, seven exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval, 1.3 to 8.8, six exposed infants). - Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations. - If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS: Discontinuation of Treatment with Paroxetine Hydrochloride). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options. Animal Findings - Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. Nonteratogenic Effects - Neonates exposed to paroxetine hydrochloride and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome). - Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including paroxetine hydrochloride) in pregnancy and PPHN. Other studies do not show a significant statistical association. - Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. - When treating a pregnant woman with paroxetine hydrochloride, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see ADMINISTRATION and ADVERSE REACTIONS: Post-Marketing Reports). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Paroxetine in women who are pregnant. ### Labor and Delivery - The effect of paroxetine on labor and delivery in humans is unknown. ### Nursing Mothers - Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when paroxetine hydrochloride is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with immediate-release paroxetine hydrochloride, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine hydrochloride in a child or adolescent must balance the potential risks with the clinical need. Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as paroxetine tablets. - In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine hydrochloride and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. - Events reported upon discontinuation of treatment with paroxetine hydrochloride in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine hydrochloride and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see DOSAGE AND ADMINISTRATION: Discontinuation of Treatment with Paroxetine Tablets). ### Geriatic Use - SSRIs and SNRIs, including paroxetine hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS:Hyponatremia). - In worldwide premarketing clinical trials with paroxetine hydrochloride, 17% of patients treated with paroxetine hydrochloride (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). ### Gender - There is no FDA guidance on the use of Paroxetine with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Paroxetine with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Paroxetine in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Paroxetine in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Paroxetine in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Paroxetine in patients who are immunocompromised. # Administration and Monitoring ### Administration Major Depressive Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least one week. Maintenance Therapy - There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. - Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for periods of up to one year with doses that averaged about 30 mg. Obsessive Compulsive Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least one week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day. Maintenance Therapy - Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Panic Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The target dose of paroxetine tablets in the treatment of panic disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least one week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets. The maximum dosage should not exceed 60 mg/day. Maintenance Therapy - Long-term maintenance of efficacy was demonstrated in a 3 month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Social Anxiety Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of paroxetine tablets has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY: Clinical Trials). Maintenance Therapy - There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Generalized Anxiety Disorder Usual Initial Dosage - Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least one week. Maintenance Therapy - Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine tablets during an 8 week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Special Populations Treatment of Pregnant Women During the Third Trimester - Neonates exposed to paroxetine tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or Hepatic Impairment - The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day. Switching a Patient to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders - At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with paroxetine tablets. Conversely, at least 14 days should be allowed after stopping paroxetine tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of Paroxetine Tablets with Other MAOIs Such as Linezolid or Methylene Blue - Do not start paroxetine tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS). - In some cases, a patient already receiving therapy with paroxetine tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, paroxetine tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with paroxetine tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS). - The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with paroxetine tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS). Discontinuation of Treatment with Paroxetine Tablets - Symptoms associated with discontinuation of paroxetine tablets have been reported (see PRECAUTIONS: Discontinuation of Treatment with Paroxetine Hydrochloride). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine tablets is being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. ### Monitoring - There is limited information regarding Monitoring of Paroxetine in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Paroxetine in the drug label. # Overdosage Human Experience - Since the introduction of paroxetine hydrochloride in the United States, 342 spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or the presence of significant comorbid conditions. Of 145 nonfatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered. - Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including Torsades de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention. Overdosage Management - No specific antidotes for paroxetine are known. Treatment should consist of those general measures employed in the management of overdosage with any drugs effective in the treatment of major depressive disorder. - Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion or exchange transfusion are unlikely to be of benefit. - A specific caution involves patients who are taking or have recently taken paroxetine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see PRECAUTIONS: Drug Interactions: Drugs Metabolized by Cytochrome CYP2D6). - In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR). # Pharmacology ## Mechanism of Action - ## Structure - Paroxetine hydrochloride is an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (3S-trans)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-piperidine hydrochloride hemihydrate and has the molecular formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride is: - Paroxetine hydrochloride (hemihydrate), USP is an odorless, white or almost white crystalline powder, having a melting point range of 129° to 131°C and a solubility of 5.4 mg/mL in water. - Each film-coated tablet contains paroxetine hydrochloride hemihydrate equivalent to 10 mg, 20 mg, 30 mg or 40 mg paroxetine. Inactive ingredients consist of dibasic calcium phosphate dihydrate, FD&C Blue No. 1 Aluminum Lake, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, sodium starch glycolate, titanium dioxide and triacetin. - Paroxetine hydrochloride complies with USP Chromatographic Purity Test 1. ## Pharmacodynamics - The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and generalized anxiety disorder (GAD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic, and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. - Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially inactive. ## Pharmacokinetics - Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of paroxetine hydrochloride daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers). - In a meta analysis of paroxetine from four studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower Cmax or AUC than females. Absorption and Distribution - Paroxetine is equally bioavailable from the oral suspension and tablet. - Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady-state, mean values of Cmax, Tmax, Cmin, and T1/2were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21 hours (CV 32%), respectively. The steady-state Cmax and Cmin values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that one of the enzymes that metabolizes paroxetine is readily saturable. - The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. - Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. - Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin. Metabolism and Excretion - The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of paroxetine hydrochloride. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. - Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS: Drug Interactions: Drugs Metabolized by CYP2D6). - Approximately 64% of a 30 mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10 day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10 day post-dosing period. Other Clinical Pharmacology Information Specific Populations Renal and Liver Disease - Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min were approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, Cmax). - The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE AND ADMINISTRATION). Elderly Patients - In a multiple-dose study in the elderly at daily paroxetine doses of 20 mg, 30 mg, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND ADMINISTRATION). Drug-Drug Interactions - In vitro drug interaction studies reveal that paroxetine inhibits CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine (see PRECAUTIONS: Drug Interactions). Clinical Trials Major Depressive Disorder - The efficacy of paroxetine hydrochloride as a treatment for major depressive disorder has been established in six placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, paroxetine hydrochloride was shown to be significantly more effective than placebo in treating major depressive disorder by at least two of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine hydrochloride was significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. - A study of outpatients with major depressive disorder who had responded to paroxetine hydrochloride (HDRS total score <8) during an initial 8-week open-treatment phase and were then randomized to continuation on paroxetine hydrochloride or placebo for one year demonstrated a significantly lower relapse rate for patients taking paroxetine hydrochloride (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients. Obsessive Compulsive Disorder - The effectiveness of paroxetine hydrochloride in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients were treated with fixed doses of 20 mg, 40 mg, or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40 mg and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40 mg and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing paroxetine (20 mg to 60 mg daily) with clomipramine (25 mg to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. - The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1. - Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. - The long-term maintenance effects of paroxetine hydrochloride in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. Panic Disorder - The effectiveness of paroxetine hydrochloride in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1 to 3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine hydrochloride was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. - Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients. - Study 2 was a 12-week flexible-dose study comparing paroxetine (10 mg to 60 mg daily) and placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients. - Study 3 was a 12-week flexible-dose study comparing paroxetine (10 mg to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients. - In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine. - Long-term maintenance effects of paroxetine hydrochloride in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. - Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. Social Anxiety Disorder - The effectiveness of paroxetine hydrochloride in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of paroxetine hydrochloride compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS). - Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients, respectively. - Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day. - Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender. Generalized Anxiety Disorder - The effectiveness of paroxetine hydrochloride in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV). - Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine hydrochloride were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose. - Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine hydrochloride demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of paroxetine hydrochloride over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. - Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. - In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of paroxetine hydrochloride, were randomized to continuation of paroxetine hydrochloride at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of ≥ 2 points compared to baseline on the CGI-Severity of Illness scale, to a score of ≤ 3. Relapse during the double-blind phase was defined as an increase of ≥ 2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥ 4, or withdrawal due to lack of efficacy. Patients receiving continued paroxetine hydrochloride experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Two year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, and GAD on a mg/m2 basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg vs. 60 mg), the doses used in these carcinogenicity studies were only 2 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown. Mutagenesis - Paroxetine produced no genotoxic effects in a battery of five in vitro and two in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats. Impairment of Fertility - Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men. - A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD or 2.4 times the MRHD for OCD on a mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2 basis). # Clinical Studies - There is limited information regarding Clinical Studies of Paroxetine in the drug label. # How Supplied - Paroxetine Tablets, USP are available as 10 mg, 20 mg, 30 mg and 40 mg tablets. - The 10 mg tablet is a blue film-coated, modified capsule-shaped, scored tablet debossed with M on one side of the tablet and N to the left of the score and 1 to the right of the score on the other side. They are available as follows: - NDC 0378-7001-93 - bottles of 30 tablets - NDC 0378-7001-10 - bottles of 1000 tablets - The 20 mg tablet is a blue film-coated, modified capsule-shaped, scored tablet debossed with M on one side of the tablet and N to the left of the score and 2 to the right of the score on the other side. They are available as follows: - NDC 0378-7002-93 - bottles of 30 tablets - NDC 0378-7002-10 - bottles of 1000 tablets - The 30 mg tablet is a blue film-coated, round, unscored tablet debossed with M over N3 on one side of the tablet and blank on the other side. They are available as follows: - NDC 0378-7003-93 - bottles of 30 tablets - NDC 0378-7003-10 - bottles of 1000 tablets - The 40 mg tablet is a blue film-coated, round, unscored tablet debossed with M over N4 on one side of the tablet and blank on the other side. They are available as follows: - NDC 0378-7004-93 - bottles of 30 tablets - NDC 0378-7004-10 - bottles of 1000 tablets ## Storage - Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Information for Patients - Paroxetine tablets should not be chewed or crushed, and should be swallowed whole. - Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine hydrochloride and triptans, tramadol, or other serotonergic agents. - Patients should be advised that taking paroxetine hydrochloride can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. - Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine hydrochloride and should counsel them in its appropriate use. A patient Medication Guide is available for paroxetine hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. - Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine hydrochloride. Clinical Worsening and Suicide Risk - Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin and Warfarin) - Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Interference with Cognitive and Motor Performance - Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine hydrochloride has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine hydrochloride does not affect their ability to engage in such activities. Completing Course of Therapy - While patients may notice improvement with treatment with paroxetine hydrochloride in 1 to 4 weeks, they should be advised to continue therapy as directed. Concomitant Medication - Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol - Although paroxetine hydrochloride has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine hydrochloride. Pregnancy - Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic Effects and Nonteratogenic Effects). Nursing - Patients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS: Nursing Mothers). # Precautions with Alcohol - Alcohol-Paroxetine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Paxil, Paxil CR. # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Aropax
55189f6537e4d8b8bfa6578fcbed66053ff38d96	wikidoc	Artemether	Artemether # Overview Artemether (INN) is an antimalarial for the treatment of multi-drug resistant strains of falciparum malaria. Its combination (co-formulation) with Lumefantrine has first been marketed by Novartis under the brand names Riamet and Coartem. Today, this combination therapy is available as generic from several manufacturers. # Category Antimalarial # US Brand Names COARTEM® # FDA Package Insert Description # Mechanisms of Action The specific mechanism of action of artemisinin is not well understood, and there is ongoing research directed at elucidating it. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin and liberates free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death. Numerous studies have investigated the type of damage that these oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. They found artemisinin to be a potent inhibitor of hemeozoin formation activity of malaria parasite. A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane. Artemisinins have also been shown to inhibit PfATP6, a SERCA-type enzyme (calcium transporter) and artemisinin has been shown to compete with thapsigargin for SERCA binding, though artemesinin is much less toxic to mammalian cells. Resistance to artemisinin is conferred by a single mutation in the calcium transporter (PfATP6). This mutation has been studied in the laboratory but recently a study from French Guiana in field isolates of malaria parasites has identified a different mutation in the calcium transporter (PfATP6) that is associated with resistance to artemether, lending support to the idea that PfATP6 is the target for artemisinins.	Artemether Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2] # Overview Artemether (INN) is an antimalarial for the treatment of multi-drug resistant strains of falciparum malaria. Its combination (co-formulation) with Lumefantrine has first been marketed by Novartis under the brand names Riamet and Coartem. Today, this combination therapy is available as generic from several manufacturers. # Category Antimalarial # US Brand Names COARTEM® # FDA Package Insert Description # Mechanisms of Action The specific mechanism of action of artemisinin is not well understood, and there is ongoing research directed at elucidating it. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin and liberates free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death.[1] Numerous studies have investigated the type of damage that these oxygen radicals may induce. For example, Pandey et al. have observed inhibition of digestive vacuole cysteine protease activity of malarial parasite by artemisinin.[2] These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. They found artemisinin to be a potent inhibitor of hemeozoin formation activity of malaria parasite. A 2005 study investigating the mode of action of artemisinin using a yeast model demonstrated that the drug acts on the electron transport chain, generates local reactive oxygen species, and causes the depolarization of the mitochondrial membrane.[3] Artemisinins have also been shown to inhibit PfATP6, a SERCA-type enzyme (calcium transporter) and artemisinin has been shown to compete with thapsigargin for SERCA binding, though artemesinin is much less toxic to mammalian cells. Resistance to artemisinin is conferred by a single mutation in the calcium transporter (PfATP6). This mutation has been studied in the laboratory but recently a study from French Guiana in field isolates of malaria parasites has identified a different mutation in the calcium transporter (PfATP6) that is associated with resistance to artemether, lending support to the idea that PfATP6 is the target for artemisinins.[4]	https://www.wikidoc.org/index.php/Artemether
3475ed5e7e9486512305ef7729bf61db63ecdfb9	wikidoc	Vasa recta	Vasa recta In the blood supply of the kidney, the vasa recta renis (or straight arteries of kidney, or straight arterioles of kidney) form a series of straight capillaries (recta is from the Latin for "straight") that descend from the cortex into the medulla. These vessels branch off of the efferent arterioles of juxtamedullary nephrons (those nephrons closest to the medulla), enter the medulla, and surround the loop of Henle. # Histology On a slide, vasa recta can be distinguished from the tubules of the loop of Henle by the presence of blood. # Function Each of the vasa recta has a hairpin turn in the medulla and carries blood at a very slow rate, two factors crucial in the maintenance of countercurrent exchange that prevent washout of the concentration gradients established in the renal medulla. The maintenance of this concentration gradient is one of the components responsible for the kidney's ability to produce concentrated urine. # Nomenclature According to Terminologia Anatomica, the term "vasa recta renis" is an alternate name for "arteriolae rectae renis", and a separate term, venulae rectae renis, is used to identify the venous portion. However, other sources consider "vasa recta renis" to refer to both the arterial and venous portions. The "renis" is often omitted, but there do exist two other structures with the same name: - vasa recta (intestines) (in the ileum and jejunum) - the straight portion of the seminiferous tubule # Pathology The slow blood flow in vasa recta makes them a likely place of thrombosis in hypercoagulable states, or erythrocyte sickling in sickle cell disease. Ischemia that results may lead to renal papillary necrosis.	Vasa recta Template:Infobox Artery In the blood supply of the kidney, the vasa recta renis (or straight arteries of kidney, or straight arterioles of kidney) form a series of straight capillaries (recta is from the Latin for "straight") that descend from the cortex into the medulla. These vessels branch off of the efferent arterioles of juxtamedullary nephrons (those nephrons closest to the medulla), enter the medulla, and surround the loop of Henle. # Histology On a slide, vasa recta can be distinguished from the tubules of the loop of Henle by the presence of blood.[1] # Function Each of the vasa recta has a hairpin turn in the medulla and carries blood at a very slow rate, two factors crucial in the maintenance of countercurrent exchange that prevent washout of the concentration gradients established in the renal medulla.[2] The maintenance of this concentration gradient is one of the components responsible for the kidney's ability to produce concentrated urine. # Nomenclature According to Terminologia Anatomica[3], the term "vasa recta renis" is an alternate name for "arteriolae rectae renis", and a separate term, venulae rectae renis, is used to identify the venous portion. However, other sources consider "vasa recta renis" to refer to both the arterial and venous portions.[4] The "renis" is often omitted, but there do exist two other structures with the same name: - vasa recta (intestines) (in the ileum and jejunum)[5] - the straight portion of the seminiferous tubule[6] # Pathology The slow blood flow in vasa recta makes them a likely place of thrombosis in hypercoagulable states, or erythrocyte sickling in sickle cell disease. Ischemia that results may lead to renal papillary necrosis.	https://www.wikidoc.org/index.php/Arteriolae_recti
7dc0d0c54862bfc8e7c1e2f6b6731c3301429463	wikidoc	Artesunate	Artesunate Artesunate (INN) is part of the artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of artemisinin that is water-soluble and may therefore be given by injection. It is sometimes abbreviated AS. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system. # Medical uses The World Health Organization recommends intramuscular or intravenous artesunate as the first line treatment for severe malaria. Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa and Asia. A subsequent systematic review of seven randomized controlled trials found this beneficial effect to be consistent across all trials. For severe malaria during pregnancy, there is less certainty about the safety of artesunate during the first trimester but artesunate is recommended as first-line therapy during the second and third trimesters. Artesunate is also used to treat less severe forms of malaria when it can be given orally, but should always be taken with a second antimalarial such as mefloquine or amodiaquine to avoid the development of resistance. While artesunate is used primarily as treatment for malaria, there is some evidence that it may also have some beneficial effects in Schistosoma haematobium infection, but this needs confirming in large randomized trials. # Adverse effects Artesunate is generally safe and well-tolerated. The best recognised side effect of the artemesinins that they lower reticulocyte counts. This is not usually of clinical relevance. Delayed haemolysis (occurring around two weeks after treatment) has been observed in patients treated with artesunate for severe malaria. Whether or not this haemolysis is due to artesunate, or to the malaria itself is unclear. The safety of artesunate in pregnancy is unclear. There is evidence of embryotoxicity in animal models (defects in long bones and ventricular septal defects in the heart in rats and monkeys). However, observational evidence from 123 human first-trimester pregnancies showed no evidence of damage to the fetus. # Synthesis Artesunate is prepared from dihydroartemisinin (DHA) by reacting it with succinic acid anhydride in basic medium. Pyridine as base/solvent, sodium bicarbonate in chloroform and catalyst DMAP (N,N-dimethylaminopyridine) and triethylamine in 1,2-dichloroethane have been used, with yields of up to 100%. A large scale process involves treatment of DHA in dichloromethane with a mixture of pyridine, a catalytic amount of DMAP and succinic anhydride. The dichloromethane mixture is stirred for 6–9 h to get artesunate in quantitative yield. The product is further re-crystallized from dichloromethane. alpha-Artesunate is exclusively formed (m.p 135–137˚C). # Mechanisms of action In a hematin dependent manner, artesunate has been shown to potently inhibit the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase. # Drug resistance Clinical evidence of drug resistance has appeared in Western Cambodia, where artemisinin monotherapy is common. There are as yet no reports of resistance emerging elsewhere.	Artesunate Artesunate (INN) is part of the artemisinin group of drugs that treat malaria. It is a semi-synthetic derivative of artemisinin that is water-soluble and may therefore be given by injection. It is sometimes abbreviated AS. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[1] # Medical uses The World Health Organization recommends intramuscular or intravenous artesunate as the first line treatment for severe malaria.[2] Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa[3] and Asia.[4] A subsequent systematic review of seven randomized controlled trials found this beneficial effect to be consistent across all trials.[5] For severe malaria during pregnancy, there is less certainty about the safety of artesunate during the first trimester but artesunate is recommended as first-line therapy during the second and third trimesters.[6] Artesunate is also used to treat less severe forms of malaria when it can be given orally, but should always be taken with a second antimalarial such as mefloquine or amodiaquine to avoid the development of resistance.[2] While artesunate is used primarily as treatment for malaria, there is some evidence that it may also have some beneficial effects in Schistosoma haematobium infection,[7] but this needs confirming in large randomized trials. # Adverse effects Artesunate is generally safe and well-tolerated. The best recognised side effect of the artemesinins that they lower reticulocyte counts.[8] This is not usually of clinical relevance. Delayed haemolysis (occurring around two weeks after treatment) has been observed in patients treated with artesunate for severe malaria.[9] Whether or not this haemolysis is due to artesunate, or to the malaria itself is unclear.[10] The safety of artesunate in pregnancy is unclear. There is evidence of embryotoxicity in animal models (defects in long bones and ventricular septal defects in the heart in rats and monkeys). However, observational evidence from 123 human first-trimester pregnancies showed no evidence of damage to the fetus.[11] # Synthesis Artesunate is prepared from dihydroartemisinin (DHA) by reacting it with succinic acid anhydride in basic medium. Pyridine as base/solvent, sodium bicarbonate in chloroform and catalyst DMAP (N,N-dimethylaminopyridine) and triethylamine in 1,2-dichloroethane have been used, with yields of up to 100%. A large scale process involves treatment of DHA in dichloromethane with a mixture of pyridine, a catalytic amount of DMAP and succinic anhydride. The dichloromethane mixture is stirred for 6–9 h to get artesunate in quantitative yield. The product is further re-crystallized from dichloromethane. alpha-Artesunate is exclusively formed (m.p 135–137˚C). # Mechanisms of action In a hematin dependent manner, artesunate has been shown to potently inhibit the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase.[12] # Drug resistance Clinical evidence of drug resistance has appeared in Western Cambodia, where artemisinin monotherapy is common.[13] There are as yet no reports of resistance emerging elsewhere.	https://www.wikidoc.org/index.php/Artesunate
23f118b5e4711fd07fdec8f554efeaffb0f9ce48	wikidoc	Asafoetida	Asafoetida Asafoetida (Ferula assafoetida), alternative spelling asafetida, Template:PronEng (also known as devil's dung, stinking gum, asant, food of the gods, hing, Hilteet, and giant fennel) is a species of Ferula native to Iran. It is an herbaceous perennial plant growing to 2 m tall, with stout, hollow, somewhat succulent stems 5-8 cm diameter at the base of the plant. The leaves are 30–40 cm long, tripinnate or even more finely divided, with a stout basal sheath clasping the stem. The flowers are yellow, produced in large compound umbels. Asafoetida has a foul smell when raw, but in cooked dishes, it delivers a smooth flavor, reminiscent of leeks. # Uses ## Cooking This spice is used as a digestive aid, in food as a condiment and in pickles. Its odor is so strong that it must be stored in airtight containers; otherwise the aroma, which is nauseating in quantities, will contaminate other spices stored nearby. However, its odour and flavor become much milder and more pleasant upon heating in oil or ghee, acquiring a taste and aroma reminiscent of sautéed onion and garlic. In India, it is used especially by the merchant caste of the Hindus and by adherents of Jainism, who do not eat onions or garlic. It is used in most vegetarian and lentil dishes to both add flavor and aroma and reduce flatulence. It is mainly grown in Iran, Afghanistan. The Indian companies Laljee Godhoo, Laxmi Hing (R M Kanani & Co - Gujarat) are the world's largest producers of compounded asafoetida. ## Impact on health & medical applications Asafetida has certain medicinal uses and most commonly is used as a digestive aid. It is reputed to lessen flatulence and is often added to lentil or eggplant dishes in small quantities. It is also said to be helpful in cases of asthma and bronchitis. A folk tradition remedy for children's colds: it is mixed into a foul-smelling paste and hung in a bag around the afflicted child's neck. In Thailand it is used to aid babies' digestion and is smeared on the child's stomach in an alcohol tincture known as "mahahing." John C Duval reported in 1936 that the odor of asafetida is attractive to the wolf, a matter of common knowledge, he says, along the Texas/Mexican border. Asafetida has also been reported to have contraceptive/abortifacient activity , and is related (and considered an inferior substitute to) the ancient Ferula species Silphium. Asafoetida oleo-gum-resin has been reported to be antiepileptic in classical Unani as well as ethnobotanical literature. ## Other practical or spiritual uses It is also used as one of several possible scent baits, most notably for catfish and pike. In Jamaica, asafetida is traditionally applied to a baby's anterior fontanel (Jamaican patois "mole") in order to prevent spirits (Jamaican patois "duppies") from entering the baby through the fontanel. # History It was familiar in the early Mediterranean, having come by land across Iran, and was popular in any self-respecting Classical kitchen. Though it is generally forgotten now in Europe, it is still widely used in India (commonly known there as hing). It emerged into Europe from a conquering expedition of Alexander the Great, who after returning from a trip to north-eastern Persia (modern Afghanistan), thought they had found a plant almost identical to the famed silphium of Cyrene in north Africa -- though less tasty. Dioscorides, in the first century, wrote that, "the Cyrenaic kind, even if one just tastes it, at once arouses a humour throughout the body and has a very healthy aroma, so that it is not noticed on the breath, or only a little; but the Median is weaker in power and has a nastier smell." Nevertheless, it could be substituted for silphium in cooking, which was fortunate, because a few decades after Dioscorides time, the true silphium of Cyrene went extinct, and Asafoetida gained in popularity, by physicians as well as cooks. After the Roman Empire fell, until the 16th century, asafoetida was rare in Europe, and if ever encountered, is was viewed as a medicine. "If used in cookery, it would ruin every dish because of its dreadful smell," asserted García de Orta's European guest. Nonsense, García replies, "nothing is more widely used in every part of India, both in medicine and in cookery. All the Hindus who can afford it buy it to add to their food. The rich Brahmins, and all the Hindus who are vegetarian, eat a lot of it. They add it to their vegetables and herbs, and first rubbing the cooking put with it: it is seasoning, sauce, and condiment in every dish they eat." # Cultivation and manufacture The resin-like gum which comes from the dried sap extracted from the stem and roots is used as a spice. The resin is grayish-white when fresh, but dries to a dark amber color. The asafetida resin is difficult to grate, and is traditionally crushed between stones or with a hammer. Today, the most commonly available form is compounded asafetida, a fine powder containing 30% asafetida resin, along with rice flour and gum arabic. Ferula assafoetida is an herbaceous, monoecious, perennial plant of the family Umbelliferae. It grows to 2 m high with a circular mass of leaves. Flowering stems are 2.5–3 m high and 10 cm thick, with a number of schizogenous ducts in the cortex containing the resinous gum. Stem leaves have wide sheathing petioles. Compound large umbels arise from large sheaths. Flowers are pale greenish yellow. Fruits are oval, flat, thin, reddish brown and have a milky juice. Roots are thick, massive, and pulpy. It yields a resin similar to that of the stems. All parts of the plant have the distinctive fetid smell. # Composition Typical asafoetida contains about 40-64% resin, 25% endogeneous gum, 10-17% volatile oil, and 1.5-10% ash. The resin portion is known to contain asareninotannols 'A' and 'B', ferulic acid, umbelliferone and four unidentified compounds. # Etymology Asafoetida's English and scientific name is derived from the Persian word for resin (asa) and Latin foetida, which refers to its strong sulfurous odor. Its pungent odor has resulted in its being called by many unpleasant names; thus in French it is known (among other names) as Merde du Diable (Devil's Shit); in some dialects of English too it was known as Devil's Dung, and equivalent names can be found in most Germanic languages (e.g. German Teufelsdreck , Swedish Dyvelsträck, Dutch Duivelsdrek, Afrikaans Duiwelsdrek), also in Finnish Pirunpaska or Pirunpihka. In Turkish, it is known as Şeytantersi, Şeytan bökösu or Şeytanotu (the Devil's Herb). In many of the Indo-Aryan languages it is known as hing or "Heeng". Another name occurs in many Dravidian languages (e.g. Telugu Inguva, Kannada Ingu), but Tamil (perungaayam) and Malayalam kaayam come from a different root.	Asafoetida Asafoetida (Ferula assafoetida), alternative spelling asafetida, Template:PronEng [1] (also known as devil's dung, stinking gum, asant, food of the gods, hing, Hilteet, and giant fennel) is a species of Ferula native to Iran. It is an herbaceous perennial plant growing to 2 m tall, with stout, hollow, somewhat succulent stems 5-8 cm diameter at the base of the plant. The leaves are 30–40 cm long, tripinnate or even more finely divided, with a stout basal sheath clasping the stem. The flowers are yellow, produced in large compound umbels. Asafoetida has a foul smell when raw, but in cooked dishes, it delivers a smooth flavor, reminiscent of leeks. # Uses ## Cooking This spice is used as a digestive aid, in food as a condiment and in pickles. Its odor is so strong that it must be stored in airtight containers; otherwise the aroma, which is nauseating in quantities, will contaminate other spices stored nearby. However, its odour and flavor become much milder and more pleasant upon heating in oil or ghee, acquiring a taste and aroma reminiscent of sautéed onion and garlic[1]. In India, it is used especially by the merchant caste of the Hindus and by adherents of Jainism, who do not eat onions or garlic. It is used in most vegetarian and lentil dishes to both add flavor and aroma and reduce flatulence. It is mainly grown in Iran, Afghanistan. The Indian companies Laljee Godhoo, Laxmi Hing (R M Kanani & Co - Gujarat) are the world's largest producers of compounded asafoetida. ## Impact on health & medical applications Asafetida has certain medicinal uses and most commonly is used as a digestive aid. It is reputed to lessen flatulence and is often added to lentil or eggplant dishes in small quantities. It is also said to be helpful in cases of asthma and bronchitis. A folk tradition remedy for children's colds: it is mixed into a foul-smelling paste and hung in a bag around the afflicted child's neck. In Thailand it is used to aid babies' digestion and is smeared on the child's stomach in an alcohol tincture known as "mahahing." John C Duval reported in 1936 that the odor of asafetida is attractive to the wolf, a matter of common knowledge, he says, along the Texas/Mexican border. Asafetida has also been reported to have contraceptive/abortifacient activity [2] , and is related (and considered an inferior substitute to) the ancient Ferula species Silphium. Asafoetida oleo-gum-resin has been reported to be antiepileptic in classical Unani as well as ethnobotanical literature. [3] ## Other practical or spiritual uses It is also used as one of several possible scent baits, most notably for catfish and pike. In Jamaica, asafetida is traditionally applied to a baby's anterior fontanel (Jamaican patois "mole") in order to prevent spirits (Jamaican patois "duppies") from entering the baby through the fontanel. # History It was familiar in the early Mediterranean, having come by land across Iran, and was popular in any self-respecting Classical kitchen. Though it is generally forgotten now in Europe, it is still widely used in India (commonly known there as hing). It emerged into Europe from a conquering expedition of Alexander the Great, who after returning from a trip to north-eastern Persia (modern Afghanistan), thought they had found a plant almost identical to the famed silphium of Cyrene in north Africa -- though less tasty. Dioscorides, in the first century, wrote that, "the Cyrenaic kind, even if one just tastes it, at once arouses a humour throughout the body and has a very healthy aroma, so that it is not noticed on the breath, or only a little; but the Median [Iranian] is weaker in power and has a nastier smell." Nevertheless, it could be substituted for silphium in cooking, which was fortunate, because a few decades after Dioscorides time, the true silphium of Cyrene went extinct, and Asafoetida gained in popularity, by physicians as well as cooks. [4] After the Roman Empire fell, until the 16th century, asafoetida was rare in Europe, and if ever encountered, is was viewed as a medicine. "If used in cookery, it would ruin every dish because of its dreadful smell," asserted García de Orta's European guest. Nonsense, García replies, "nothing is more widely used in every part of India, both in medicine and in cookery. All the Hindus who can afford it buy it to add to their food. The rich Brahmins, and all the Hindus who are vegetarian, eat a lot of it. They add it to their vegetables and herbs, and first rubbing the cooking put with it: it is seasoning, sauce, and condiment in every dish they eat."[4] # Cultivation and manufacture The resin-like gum which comes from the dried sap extracted from the stem and roots is used as a spice. The resin is grayish-white when fresh, but dries to a dark amber color. The asafetida resin is difficult to grate, and is traditionally crushed between stones or with a hammer. Today, the most commonly available form is compounded asafetida, a fine powder containing 30% asafetida resin, along with rice flour and gum arabic. Ferula assafoetida is an herbaceous, monoecious, perennial plant of the family Umbelliferae. It grows to 2 m high with a circular mass of leaves. Flowering stems are 2.5–3 m high and 10 cm thick, with a number of schizogenous ducts in the cortex containing the resinous gum. Stem leaves have wide sheathing petioles. Compound large umbels arise from large sheaths. Flowers are pale greenish yellow. Fruits are oval, flat, thin, reddish brown and have a milky juice. Roots are thick, massive, and pulpy. It yields a resin similar to that of the stems. All parts of the plant have the distinctive fetid smell.[5] # Composition Typical asafoetida contains about 40-64% resin, 25% endogeneous gum, 10-17% volatile oil, and 1.5-10% ash. The resin portion is known to contain asareninotannols 'A' and 'B', ferulic acid, umbelliferone and four unidentified compounds. [6] # Etymology Asafoetida's English and scientific name is derived from the Persian word for resin (asa) and Latin foetida, which refers to its strong sulfurous odor. Its pungent odor has resulted in its being called by many unpleasant names; thus in French it is known (among other names) as Merde du Diable (Devil's Shit); in some dialects of English too it was known as Devil's Dung, and equivalent names can be found in most Germanic languages (e.g. German Teufelsdreck [7], Swedish Dyvelsträck, Dutch Duivelsdrek, Afrikaans Duiwelsdrek), also in Finnish Pirunpaska or Pirunpihka. In Turkish, it is known as Şeytantersi, Şeytan bökösu or Şeytanotu (the Devil's Herb). In many of the Indo-Aryan languages it is known as hing or "Heeng". Another name occurs in many Dravidian languages (e.g. Telugu Inguva, Kannada Ingu), but Tamil (perungaayam) and Malayalam kaayam come from a different root.	https://www.wikidoc.org/index.php/Asafetida
be18c1129835af720a0691a4c0beaa86221883c3	wikidoc	Ascaridida	Ascaridida The order Ascaridida includes several families of parasitic roundworms with three "lips" on the anterior end. They are sometimes placed in the subclass Rhabditia, but more often in the Spiruria. Important families include: - Ascarididae, which includes the giant intestinal roundworm and related species. - Toxocaridae, which includes parasites of canids, felids, and raccoons, but which can unsuccessfully parasitize humans and cause visceral larva migrans. - Anisakidae, also called the marine mammal Ascarids. The larvae of these worms cause anisakiasis when ingested by humans, but do not reproduce.	Ascaridida The order Ascaridida includes several families of parasitic roundworms with three "lips" on the anterior end. They are sometimes placed in the subclass Rhabditia, but more often in the Spiruria. Important families include: - Ascarididae, which includes the giant intestinal roundworm and related species. - Toxocaridae, which includes parasites of canids, felids, and raccoons, but which can unsuccessfully parasitize humans and cause visceral larva migrans. - Anisakidae, also called the marine mammal Ascarids. The larvae of these worms cause anisakiasis when ingested by humans, but do not reproduce.	https://www.wikidoc.org/index.php/Ascaridida
83b8835e90f7631a37e94e5025685954f5bbcb6a	wikidoc	Asian Koel	Asian Koel The Asian Koel (Eudynamys scolopacea), formerly also Common Koel, is a member of the cuckoo order of birds, the Cuculiformes, which also includes such birds as the roadrunners, the anis, and couas. It is found from southern Asia, China, and into Australia. Like many cuckoos, it lays its eggs in other birds' nests. The word koel also means "nightingale" in India because of the Indian Koel's melodious call. It is also colloquially known as the Rainbird or Stormbird in eastern Australia, as its call is supposed to foreshadow rain. # Description The Asian Koel is a large, long-tailed, cuckoo at 45 cm. The male is bluish-black, with a pale green bill, rich red eyes, and grey legs and feet. The female is brownish above and whitish below, but is heavily striped and spotted brown on the underparts and white on the upperparts. She has an olive or green beak and red eyes. Koels are very vocal, with a number of different calls. # Subspecies About fifteen subspecies are recognized: - Eudynamys scolopacea scolopacea (Linnaeus, 1758); Pakistan, India, Nepal, Sri Lanka, Laccadives, Maldives; - Eudynamys scolopacea chinensis (Cabanis and Heine,1863); southern China, continental Indochina; - Eudynamys scolopacea harterti (Ingram, 1912); Hainan; - Eudynamys scolopacea malayana (Cabanis and Heine, 1863); S Burma,Thailand, Malay Peninsula, Sumatra, Bangka, Lesser Sundas, Lombok,Sumbawa, Satonda, ?Komodo, Flores, Besar, Paloe),Borneo; - Eudynamys scolopacea mindanensis (Linnaeus,1766) (includes E. s. paraguena (Hachisuka, 1934),from Palawan, and E. s. corvina (Stresemann, 1931),from Halmahera); the Philippines (including Palawan and Babuyanes Islands), islands NE of Sulawesi (Talaud Islands (Karakelong,Lirung), Sangihe, Siau, Ruang, Manterawu); northern Moluccas (Morotai, Halmahera, Ternate, Tidore, Moti, Bacan); - Eudynamys scolopacea rufiventer (Lesson, 1830); New Guinea (except southern Irian Jaya); - Eudynamys scolopacea minima van Oordt 1911;southwestern New Guinea; - Eudynamys scolopacea salvadorii Hartert, 1900; Bismarck Archipelago; - Eudynamys scolopacea hybrida Diamond, 2000;Long Island, between New Guinea and New Britain; - Eudynamys scolopacea alberti Rothschild and Hartert, 1907; Solomon Islands; - Eudynamys scolopacrea melanorhyncha S. Müller, 1843; Sulawesi, Banggai, Muna, Togian Islands, Peleng and Sula Islands (Taliabu, Seho); - Eudynamys scolopacea orientalis (Linnaeus, 1766)(includes E. s. picata S. Müller, 1843); C and S Moluccas (Buru, Manipa, Kelang, Seram, Ambon, Tujuh,Watubela Islands); - Eudynamys scolopacea everetti Hartert 1900; Sumba to Timor and Roma, Kai Islands; - Eudynamys scolopacea cyanocephala (Latham 1801);Torres Strait islands north to Boigu and Darnley, N and E Queensland, west to the lower Norman River and north to Cape York and islands off the east coast as far as the Capricorn group, and in New South Wales; - Eudynamys scolopacea subcyanocephala Mathews, 1912; northern Australia (Western Australia, Northern Territories, western Queensland south to Mt Isa and Dolomote and east to the Cloncurry); migrant to New Guinea. # Distribution and habitat The Asian Koel is a bird of light woodland and cultivation. It is a mainly resident breeder in tropical southern Asia from India and Sri Lanka to south China and Australasia. Birds at the fringes of the range, such as much of Eastern Australia, and on high ground are summer visitors, migrating to warmer areas in winter. They have great potential in colonizing new areas. They first arrived in Singapore in the 1980s and became very common birds. # Behaviour It is a brood parasite, and lays its single egg in the nests of a variety of birds, including the Jungle Crow, House Crow and various species of honeyeaters. May also parasitize Black-headed Orioles. The young Koel does not always evict its host's chicks, and initially calls like a crow. The adult koels however may not be leaving their offspring alone entirely: The Indian koel (E. honorata) is the rain - bird of India. The bird is parasitic on crows, and it would appear from the notes of naturalists in India that the koels must look after their offspring to a certain extent, for they have been seen feeding their own young ones after they have left the nest. This behaviour of brood parasites feeding their young has been noted in several other species. The note alluded to by Richard Lydekker is probably that of A. O. Hume which was noted by Fulton in 1904. ## Diet The Asian Koel is omnivorous, consuming a variety of insects, caterpillars, eggs and small vertebrates. Adults predominanty feed on fruit. It has occasionally been known to take eggs of small birds. - Immature in Kolkata, West Bengal, India. Immature in Kolkata, West Bengal, India. - Male in Kolkata, West Bengal, India. Male in Kolkata, West Bengal, India. - Male in Kolkata, West Bengal, India. Male in Kolkata, West Bengal, India. - Male in Kolkata, West Bengal, India. Male in Kolkata, West Bengal, India. - Koel Male Koel Male - Calling male Calling male - Eating Ficus Fruit Eating Ficus Fruit - Koel Female Koel Female # Notes - ↑ Jump up to: 1.0 1.1 Payne, R. B. 2005. The Cuckoos. Oxford University Press. - ↑ Goodwin D. (1983). Crows of the World. Queensland University Press, St Lucia, Qld. ISBN 0-7022-1015-3..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Sethi, V. K., Saxena, V and Bhatt, D. 2006. An instance of the Asian Koel Eudynamys scolopacea destroying the nest of a Black-headed Oriole Oriolus xanthornus. Indian Birds 2(6):173-174 - ↑ Lydekker, R. (1895) The Royal Natural History. Volume 4. page 8 - ↑ Janice C. Lorenzana and Spencer G. Sealy (1998) Adult brood parasites feeding nestlings and fledglings of their own species: A review. J. Field Ornithol., 69(3):364-375 - ↑ Fulton, R. 1904. The Kohoperoa or Koekoea, Long-tailed Cuckoo (Urodynamis taitensis): an account of its habits, description of a nest containing its (supposed) egg, and a suggestion as to how the parasitic habit in birds has become established. Trans. N. Z. Inst. 36:113-148. - ↑ Uttangi, J. C. 2004. Robbing of eggs by female Koel, from the nest of Red-whiskered Bulbul (Pycnonotus jocosus). Newsletter for Birdwatchers 44 (5): 77.	Asian Koel The Asian Koel (Eudynamys scolopacea), formerly also Common Koel, is a member of the cuckoo order of birds, the Cuculiformes, which also includes such birds as the roadrunners, the anis, and couas. It is found from southern Asia, China, and into Australia. Like many cuckoos, it lays its eggs in other birds' nests. The word koel also means "nightingale" in India because of the Indian Koel's melodious call. It is also colloquially known as the Rainbird or Stormbird in eastern Australia, as its call is supposed to foreshadow rain. # Description The Asian Koel is a large, long-tailed, cuckoo at 45 cm. The male is bluish-black, with a pale green bill, rich red eyes, and grey legs and feet. The female is brownish above and whitish below, but is heavily striped and spotted brown on the underparts and white on the upperparts. She has an olive or green beak and red eyes. Koels are very vocal, with a number of different calls. # Subspecies About fifteen subspecies are recognized:[1] - Eudynamys scolopacea scolopacea (Linnaeus, 1758); Pakistan, India, Nepal, Sri Lanka, Laccadives, Maldives; - Eudynamys scolopacea chinensis (Cabanis and Heine,1863); southern China, continental Indochina; - Eudynamys scolopacea harterti (Ingram, 1912); Hainan; - Eudynamys scolopacea malayana (Cabanis and Heine, 1863); S Burma,Thailand, Malay Peninsula, Sumatra, Bangka, Lesser Sundas, Lombok,Sumbawa, Satonda, ?Komodo, Flores, Besar, Paloe),Borneo; - Eudynamys scolopacea mindanensis (Linnaeus,1766) (includes E. s. paraguena (Hachisuka, 1934),from Palawan, and E. s. corvina (Stresemann, 1931),from Halmahera); the Philippines (including Palawan and Babuyanes Islands), islands NE of Sulawesi (Talaud Islands (Karakelong,Lirung), Sangihe, Siau, Ruang, Manterawu); northern Moluccas (Morotai, Halmahera, Ternate, Tidore, Moti, Bacan); - Eudynamys scolopacea rufiventer (Lesson, 1830); New Guinea (except southern Irian Jaya); - Eudynamys scolopacea minima van Oordt 1911;southwestern New Guinea; - Eudynamys scolopacea salvadorii Hartert, 1900; Bismarck Archipelago; - Eudynamys scolopacea hybrida Diamond, 2000;Long Island, between New Guinea and New Britain; - Eudynamys scolopacea alberti Rothschild and Hartert, 1907; Solomon Islands; - Eudynamys scolopacrea melanorhyncha S. Müller, 1843; Sulawesi, Banggai, Muna, Togian Islands, Peleng and Sula Islands (Taliabu, Seho); - Eudynamys scolopacea orientalis (Linnaeus, 1766)(includes E. s. picata S. Müller, 1843); C and S Moluccas (Buru, Manipa, Kelang, Seram, Ambon, Tujuh,Watubela Islands); - Eudynamys scolopacea everetti Hartert 1900; Sumba to Timor and Roma, Kai Islands; - Eudynamys scolopacea cyanocephala (Latham 1801);Torres Strait islands north to Boigu and Darnley, N and E Queensland, west to the lower Norman River and north to Cape York and islands off the east coast as far as the Capricorn group, and in New South Wales; - Eudynamys scolopacea subcyanocephala Mathews, 1912; northern Australia (Western Australia, Northern Territories, western Queensland south to Mt Isa and Dolomote and east to the Cloncurry); migrant to New Guinea. # Distribution and habitat The Asian Koel is a bird of light woodland and cultivation. It is a mainly resident breeder in tropical southern Asia from India and Sri Lanka to south China and Australasia. Birds at the fringes of the range, such as much of Eastern Australia, and on high ground are summer visitors, migrating to warmer areas in winter. They have great potential in colonizing new areas. They first arrived in Singapore in the 1980s and became very common birds.[1] # Behaviour It is a brood parasite, and lays its single egg in the nests of a variety of birds, including the Jungle Crow,[2] House Crow and various species of honeyeaters. May also parasitize Black-headed Orioles.[3] The young Koel does not always evict its host's chicks, and initially calls like a crow. The adult koels however may not be leaving their offspring alone entirely: The Indian koel (E. honorata) is the rain - bird of India. The bird is parasitic on crows, and it would appear from the notes of naturalists in India that the koels must look after their offspring to a certain extent, for they have been seen feeding their own young ones after they have left the nest. This behaviour of brood parasites feeding their young has been noted in several other species.[5] The note alluded to by Richard Lydekker is probably that of A. O. Hume which was noted by Fulton in 1904.[6] ## Diet The Asian Koel is omnivorous, consuming a variety of insects, caterpillars, eggs and small vertebrates. Adults predominanty feed on fruit. It has occasionally been known to take eggs of small birds.[7] Template:Listen - Immature in Kolkata, West Bengal, India. Immature in Kolkata, West Bengal, India. - Male in Kolkata, West Bengal, India. Male in Kolkata, West Bengal, India. - Male in Kolkata, West Bengal, India. Male in Kolkata, West Bengal, India. - Male in Kolkata, West Bengal, India. Male in Kolkata, West Bengal, India. - Koel Male Koel Male - Calling male Calling male - Eating Ficus Fruit Eating Ficus Fruit - Koel Female Koel Female # Notes - ↑ Jump up to: 1.0 1.1 Payne, R. B. 2005. The Cuckoos. Oxford University Press. - ↑ Goodwin D. (1983). Crows of the World. Queensland University Press, St Lucia, Qld. ISBN 0-7022-1015-3..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Sethi, V. K., Saxena, V and Bhatt, D. 2006. An instance of the Asian Koel Eudynamys scolopacea destroying the nest of a Black-headed Oriole Oriolus xanthornus. Indian Birds 2(6):173-174 - ↑ Lydekker, R. (1895) The Royal Natural History. Volume 4. page 8 - ↑ Janice C. Lorenzana and Spencer G. Sealy (1998) Adult brood parasites feeding nestlings and fledglings of their own species: A review. J. Field Ornithol., 69(3):364-375 [1] - ↑ Fulton, R. 1904. The Kohoperoa or Koekoea, Long-tailed Cuckoo (Urodynamis taitensis): an account of its habits, description of a nest containing its (supposed) egg, and a suggestion as to how the parasitic habit in birds has become established. Trans. N. Z. Inst. 36:113-148. - ↑ Uttangi, J. C. 2004. Robbing of eggs by female Koel, from the nest of Red-whiskered Bulbul (Pycnonotus jocosus). Newsletter for Birdwatchers 44 (5): 77.	https://www.wikidoc.org/index.php/Asian_Koel
d26664e98b75138770773578e25c4fbdc082b201	wikidoc	Asparagine	Asparagine # Overview Asparagine (abbreviated as Asn or N; Asx or B represent either asparagine or aspartic acid) is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side chain's functional group. It is considered a non-essential amino acid. A reaction between asparagine and reducing sugars or reactive carbonyls produces acrylamide (acrylic amide) in food when heated to sufficient temperature, i.e. baking. These occur primarily in baked goods such as french fries, potato chips, and roasted coffee. Its codons are AAU and AAC. # History Asparagine was first isolated in 1806 from asparagus juice, in which it is abundant -- hence its name -- becoming the first amino acid to be isolated. The characteristic smell observed in the urine of individuals after their consumption of asparagus is attributed to various metabolic byproducts of asparagine: in 1891, Marceli Nencki claimed that the substance responsible was methanethiol, and Robert White's 1975 research indicated that the substances were various thioesters. Other likely possibilities include asparagine aminosuccinic monoamide. Allison and McWhirter's 1956 research indicated that some individuals do not produce this odor after asparagus consumption, and that this is autosomal; however, a re-examination in 1980 showed that these individuals are, rather, not able to detect the odor. # Structural function in proteins Since the asparagine side chain can make efficient hydrogen bond interactions with the peptide backbone, asparagines are often found near the beginning and end of alpha-helices, and in turn motifs in beta sheets. Its role can be thought as "capping" the hydrogen bond interactions which would otherwise need to be satisfied by the polypeptide backbone. Glutamines have an extra methylene group, have more conformational entropy and thus are less useful in this regard. Asparagine also provides key sites for N-linked glycosylation, modification of the protein chain with the addition of carbohydrate chains. # Sources ## Dietary Sources Asparagine is not an essential amino acid, which means that it can be synthesized from central metabolic pathway intermediates in humans and is not required in the diet. Asparagine is found in: - Animal sources: dairy, beef, poultry, eggs, fish, lactalbumin, seafood - Vegetarian sources: asparagus, potatoes, legumes, nuts, seeds, soy, whey, whole grains, ## Biosynthesis The precursor to asparagine is oxaloacetate. Oxaloacetate is converted to aspartate using a transaminase enzyme. The enzyme transfers the amino group from glutamate to oxaloacetate producing α-ketoglutarate and aspartate. The enzyme asparagine synthetase produces asparagine, AMP, glutamate, and pyrophosphate from aspartate, glutamine, and ATP. In the asparagine synthetase reaction, ATP is used to activate aspartate, forming β-aspartyl-AMP. Glutamine donates an ammonium group which reacts with β-aspartyl-AMP to form asparagine and free AMP. # Degradation Aspartate is a glucogenic amino acid. L-asparaginase hydrolyzes the amide group to form aspartate and ammonium. A transaminase converts the aspartate to oxaloacetate which can then be metabolized in the citric acid cycle or gluconeogenesis. # Function The nervous system needs asparagine to maintain the equilibrium, as well as in amino acid transformation. It also plays an important role in the synthesis of ammonia.	Asparagine Template:NatOrganicBox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Asparagine (abbreviated as Asn or N; Asx or B represent either asparagine or aspartic acid) is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side chain's functional group. It is considered a non-essential amino acid. A reaction between asparagine and reducing sugars or reactive carbonyls produces acrylamide (acrylic amide) in food when heated to sufficient temperature, i.e. baking. These occur primarily in baked goods such as french fries, potato chips, and roasted coffee. Its codons are AAU and AAC.[1] # History Asparagine was first isolated in 1806 from asparagus juice, in which it is abundant -- hence its name -- becoming the first amino acid to be isolated. The characteristic smell observed in the urine of individuals after their consumption of asparagus is attributed to various metabolic byproducts of asparagine: in 1891, Marceli Nencki claimed that the substance responsible was methanethiol, and Robert White's 1975 research indicated that the substances were various thioesters. Other likely possibilities include asparagine aminosuccinic monoamide. Allison and McWhirter's 1956 research[2] indicated that some individuals do not produce this odor after asparagus consumption, and that this is autosomal; however, a re-examination in 1980 showed that these individuals are, rather, not able to detect the odor. # Structural function in proteins Since the asparagine side chain can make efficient hydrogen bond interactions with the peptide backbone, asparagines are often found near the beginning and end of alpha-helices, and in turn motifs in beta sheets. Its role can be thought as "capping" the hydrogen bond interactions which would otherwise need to be satisfied by the polypeptide backbone. Glutamines have an extra methylene group, have more conformational entropy and thus are less useful in this regard. Asparagine also provides key sites for N-linked glycosylation, modification of the protein chain with the addition of carbohydrate chains. # Sources ## Dietary Sources Asparagine is not an essential amino acid, which means that it can be synthesized from central metabolic pathway intermediates in humans and is not required in the diet. Asparagine is found in: - Animal sources: dairy, beef, poultry, eggs, fish, lactalbumin, seafood - Vegetarian sources: asparagus, potatoes, legumes, nuts, seeds, soy, whey, whole grains, ## Biosynthesis The precursor to asparagine is oxaloacetate. Oxaloacetate is converted to aspartate using a transaminase enzyme. The enzyme transfers the amino group from glutamate to oxaloacetate producing α-ketoglutarate and aspartate. The enzyme asparagine synthetase produces asparagine, AMP, glutamate, and pyrophosphate from aspartate, glutamine, and ATP. In the asparagine synthetase reaction, ATP is used to activate aspartate, forming β-aspartyl-AMP. Glutamine donates an ammonium group which reacts with β-aspartyl-AMP to form asparagine and free AMP. # Degradation Aspartate is a glucogenic amino acid. L-asparaginase hydrolyzes the amide group to form aspartate and ammonium. A transaminase converts the aspartate to oxaloacetate which can then be metabolized in the citric acid cycle or gluconeogenesis. # Function The nervous system needs asparagine to maintain the equilibrium, as well as in amino acid transformation. It also plays an important role in the synthesis of ammonia.	https://www.wikidoc.org/index.php/Asparagine
78432bdc8de723cb1ae335b5aabc7a5b6055382c	wikidoc	Astemizole	Astemizole # Overview Astemizole (marketed under the brand name Hismanal) is a second generation antihistamine drug which has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It has been withdrawn from the market in most countries because of rare but potentially fatal interactions with CYP3A4 enzyme inhibitors (e.g. erythromycin, grapefruit juice). # Pharmacology Astemizole is an histamine H1-receptor antagonist. It is structurally similar to terfenadine and haloperidol (a butyrophenone antipsychotic). It has anticholinergic and antipruritic effects. Astemizole competitively binds to histamine H1-receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema and pruritus (caused by histamine). Astemizole does not cross the blood-brain barrier, and H1 receptor binding is mostly in the peripheral rather than central nervous system (CNS depression is thus minimal). Astemizole may also act on histamine H3 receptors, thereby producing adverse effects. Astemizole is rapidly absorbed from the gastrointestinal tract; protein binding is around 96%. # Toxicity Astemizole has an oral LD50 of approximately 2052mg/kg (in mice). # Research It has been reported that this drug might prevent 97% of the muscle wasting (atrophy) that occurs in immobile, bedridden patients. Testing upon mice showed that it blocked the activity of a protein present in the muscle that is involved in muscle atrophy. Recent studies have also suggested anti-malarial properties of astemizole. However the concerns for the drug's longterm effects on the heart preclude its routine use in humans for this indication. Astemizole has recently been found to be a potent treatment for malaria. It has a mechanism of action similar to chloroquine but has activity even in chloroquine-resistant parasites.	Astemizole Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Astemizole (marketed under the brand name Hismanal) is a second generation antihistamine drug which has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It has been withdrawn from the market in most countries because of rare but potentially fatal interactions with CYP3A4 enzyme inhibitors (e.g. erythromycin, grapefruit juice). # Pharmacology Astemizole is an histamine H1-receptor antagonist. It is structurally similar to terfenadine and haloperidol (a butyrophenone antipsychotic). It has anticholinergic and antipruritic effects. Astemizole competitively binds to histamine H1-receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema and pruritus (caused by histamine). Astemizole does not cross the blood-brain barrier, and H1 receptor binding is mostly in the peripheral rather than central nervous system (CNS depression is thus minimal). Astemizole may also act on histamine H3 receptors, thereby producing adverse effects. Astemizole is rapidly absorbed from the gastrointestinal tract; protein binding is around 96%. # Toxicity Astemizole has an oral LD50 of approximately 2052mg/kg (in mice). # Research It has been reported that this drug might prevent 97% of the muscle wasting (atrophy) that occurs in immobile, bedridden patients.[1] Testing upon mice showed that it blocked the activity of a protein present in the muscle that is involved in muscle atrophy.[2] Recent studies have also suggested anti-malarial properties of astemizole. However the concerns for the drug's longterm effects on the heart preclude its routine use in humans for this indication. Astemizole has recently been found to be a potent treatment for malaria. It has a mechanism of action similar to chloroquine but has activity even in chloroquine-resistant parasites.[3] # External links - RxList.com - Astemizole - Statement on Astemizole from Health Canada # Footnotes - ↑ "Drug 'could stop muscle wasting'". NetDoctor.co.uk. 25 May,2006. Retrieved 2006-05-27. Check date values in: \|date= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Wang X, Hockerman GH, Green Iii HW, Babbs CF, Mohammad SI, Gerrard D, Latour MA, London B, Hannon KM, Pond AL (2006). "Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway". FASEB J. PMID 16723379. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ Chong CR, Chen X, Shi L, Liu JO, Sullivan DJ (2006). "A clinical drug library screen identifies astemizole as an antimalarial agent". Nat Chem Biol. 2: 415&ndash, 16. doi:10.1038/nchembio806. PMID 16816845.CS1 maint: Multiple names: authors list (link)	https://www.wikidoc.org/index.php/Astemizole
d914d357a9b2656bbd95217fedd3d4c7780710fa	wikidoc	Asteraceae	Asteraceae # Overview Asteraceae or Compositae (commonly referred to as the aster, daisy, or sunflower family), are an exceedingly large and widespread family of Angiospermae. The group has more than 23.000 currently accepted species, spread across 1620 genera and 12 subfamilies. In terms of numbers of species, Asteraceae is rivaled only by Orchidaceae. (Which of the two families is actually larger is unclear, owing to uncertainty about exactly how many species exist in each family). The main feature of the family is the composite flower type in the form of capitula surrounded by involucral bracts.The name "Asteraceae" comes from Aster, the most prominent generum in the family, that derives from the Greek ἀστήρ meaning star, and is connected with its inflorescence star form. As for the term "Compositae", more ancient but still valid, it obviously makes reference to the fact that the family is one of the few angiosperms that have composite flowers. This family has a remarkable ecological and economical importance, and is present from the polar regions to the tropics, colonizing all available habitats. The Asteraceae may represent as much as 10% of autochthon flora in many regions of the world. The largest composite genera are Senecio (1,000 species), Vernonia (1,000 species), Centaurea (700 species), Cousinia (600 species), Helichrysum (550 species), and Artemesia (550 species). Most members of Asteraceae are herbaceous, but a significant number are also shrubs, vines and trees. The family has a worldwide distribution, and is most common in the arid and semi-arid regions of subtropical and lower temperate latitudes. Asteraceae is an economically important family. Some members provide products including cooking oils, lettuce, sunflower seeds, artichokes, sweetening agents, coffee substitutes and teas. Several genera are popular with the horticultural community, including marigold, pot marigold (calendula), cone flowers, various daisies, fleabane Erigeron, chrysanthemums, dahlias, zinnias, and heleniums. Asteraceae are important in herbal medicine, including Grindelia, Echinaceae, yarrow Achillea and many others. A number of species have become weeds, including most famously in North America, dandelion Taraxacum officinale.	Asteraceae Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Asteraceae or Compositae (commonly referred to as the aster, daisy, or sunflower family), are an exceedingly large and widespread family of Angiospermae.[1] [2] The group has more than 23.000 currently accepted species, spread across 1620 genera and 12 subfamilies. In terms of numbers of species, Asteraceae is rivaled only by Orchidaceae.[1][3] (Which of the two families is actually larger is unclear, owing to uncertainty about exactly how many species exist in each family). The main feature of the family is the composite flower type in the form of capitula surrounded by involucral bracts.The name "Asteraceae" comes from Aster, the most prominent generum in the family, that derives from the Greek ἀστήρ meaning star, and is connected with its inflorescence star form. As for the term "Compositae", more ancient but still valid, it obviously makes reference to the fact that the family is one of the few angiosperms that have composite flowers.[4] This family has a remarkable ecological and economical importance, and is present from the polar regions to the tropics, colonizing all available habitats. The Asteraceae may represent as much as 10% of autochthon flora in many regions of the world. The largest composite genera are Senecio (1,000 species), Vernonia (1,000 species), Centaurea (700 species), Cousinia (600 species), Helichrysum (550 species), and Artemesia (550 species).[1] Most members of Asteraceae are herbaceous, but a significant number are also shrubs, vines and trees. The family has a worldwide distribution, and is most common in the arid and semi-arid regions of subtropical and lower temperate latitudes.[5] Asteraceae is an economically important family. Some members provide products including cooking oils, lettuce, sunflower seeds, artichokes, sweetening agents, coffee substitutes and teas. Several genera are popular with the horticultural community, including marigold, pot marigold (calendula), cone flowers, various daisies, fleabane Erigeron, chrysanthemums, dahlias, zinnias, and heleniums. Asteraceae are important in herbal medicine, including Grindelia, Echinaceae, yarrow Achillea and many others.[6] A number of species have become weeds, including most famously in North America, dandelion Taraxacum officinale.[7]	https://www.wikidoc.org/index.php/Asteraceae
3dd025f4beeb696f4e0165e5262762c9842b352b	wikidoc	Asthenopia	Asthenopia # Overview Asthenopia or eye strain is an ophthalmological condition that manifests itself through nonspecific symptoms such as fatigue, red eyes, eye strain, pain in or around the eyes, blurred vision, headache and occasional double vision. Symptoms often occur after reading, computer work, or other activities that involve tedious visual tasks. When concentrating on a visually intense task, such as continuously focusing on a book or computer monitor, the inner eye muscles may tighten, which can cause the eyes to get irritated, dry, and uncomfortable. Giving the eyes a chance to focus on a distant object at least once an hour usually alleviates the problem. Small font sizes exacerbate the strain if they cause unconscious squinting or straining to focus. On a computer, a CRT with a low refresh rate (less than 70 Hz) can cause similar problems because of the flickering image. Aging CRTs also often go slightly out of focus, and this can also cause eye strain. LCDs do not go out of focus and are less susceptible to visible flicker. Higher refresh rates and larger font sizes are worthwhile when addressing eyestrain problems. # Causes Sometimes, asthenopia can be due to specific visual problems, such as uncorrected refraction errors or binocular vision problems like accommodative insufficiency or heterophoria.	Asthenopia Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Asthenopia or eye strain is an ophthalmological condition that manifests itself through nonspecific symptoms such as fatigue, red eyes, eye strain, pain in or around the eyes, blurred vision, headache and occasional double vision. Symptoms often occur after reading, computer work, or other activities that involve tedious visual tasks. When concentrating on a visually intense task, such as continuously focusing on a book or computer monitor, the inner eye muscles may tighten, which can cause the eyes to get irritated, dry, and uncomfortable. Giving the eyes a chance to focus on a distant object at least once an hour usually alleviates the problem. Small font sizes exacerbate the strain if they cause unconscious squinting or straining to focus. On a computer, a CRT with a low refresh rate (less than 70 Hz) can cause similar problems because of the flickering image. Aging CRTs also often go slightly out of focus, and this can also cause eye strain. LCDs do not go out of focus and are less susceptible to visible flicker. Higher refresh rates and larger font sizes are worthwhile when addressing eyestrain problems. # Causes Sometimes, asthenopia can be due to specific visual problems, such as uncorrected refraction errors or binocular vision problems like accommodative insufficiency or heterophoria.	https://www.wikidoc.org/index.php/Asthenopia
7d54a9c9e3ca445fcaa4cab2851e2071c9dd4d4f	wikidoc	Astragalus	Astragalus Astragalus (As-trá-ga-lus) is a large genus of about 2,000 species of herbs and small shrubs, belonging to the legume family Fabaceae, subfamily Faboideae. The genus is native to temperate regions of the Northern Hemisphere. Common names include milk-vetch (most species) and goat's-thorn (A. gummifera, A. tragacanthus). Some pale-flowered vetches are similar in appearance, but vetches are more vine-like. Astragalus species are used as food plants by the larvae of some Lepidoptera species including the following case-bearers of the genus Coleophora: C. astragalella (feeds exclusively on A. glycyphyllos), C. cartilaginella (feeds exclusively on Astragalus), C. colutella, C. euryaula (feeds exclusively on Astragalus), C. gallipennella (feeds exclusively on A. glycyphyllos), C. hippodromica (feeds exclusively on A. gombo), C. onobrychiella (feeds exclusively on Astragalus), C. polonicella (feeds exclusively on A. arenarius) and C. vicinella. # Medicinal use Astragalus membranaceus, or huángqí (黄芪, literally "yellow leader"; also called běiqí, 北芪, literally "northern leader") is a tonic herb originally used in Chinese medicine. It is believed to be a galactagogue, and recent studies show that it may strengthen the human immune system. The natural gum tragacanth, which is used in pharmaceuticals and textiles, is obtained from Astragalus tragacanthus. It is claimed to help the immune system, and to increase the body's resistance to common viruses. In western herbal medicine, Astragalus is primarily considered a tonic for enhancing metabolism and digestion and is consumed as a tea made from the roots of the plant. It is also traditionally used to strengthen the immune system and in the healing of wounds and injuries. The biotech company Geron Corporation has determined that a molecule from Astragalus membranaceus root called TA-65 is a telomerase activator. According to PRNewswire, TA Sciences, has a license from Geron to sell TA-65 and is now selling it as a neutraceutical anti-aging product at their TA Sciences Center in New York City. # Traditional use of huang qi (radix astragali) - Replenishes the Qi of the Spleen and Stomach - Causes the Yang Qi of the Spleen and Stomach to Ascend - Benefits the Qi and consolidates the surface, controls sweating - Promotes urination and disperses swelling caused by a deficiency pattern - Promotes the discharge of pus and speeds healing - Tonifies and nourishes the Qi and Blood - Used for Wasting and Thirsting syndrome (diabetes) It enters the Lung and Spleen meridians and its properties are Sweet and Slightly Warm Contraindications: Deficient Yin with Heat, Exterior Excess Heat Notes: Prepare with Honey to tonify Spleen and Stomach Qi, with wine to tonify the essence or with salt to tonify the Kidneys. # Ornamental use Several species, including A. alpinus (bluish-purple flowers), A. hypoglottis (purple flowers) and A. lotoides, are grown as ornamental plants in gardens. # External references - Astragalus - Medicinal uses of Astragalus in Armenia - Astragalus Supplements - Astralagus information de:Tragant it:Astragalus ka:გლერძი lt:Kulkšnė sv:Astragal uk:Астрагал (рід)	Astragalus Astragalus (As-trá-ga-lus) is a large genus of about 2,000 species of herbs and small shrubs, belonging to the legume family Fabaceae, subfamily Faboideae. The genus is native to temperate regions of the Northern Hemisphere. Common names include milk-vetch (most species) and goat's-thorn (A. gummifera, A. tragacanthus). Some pale-flowered vetches are similar in appearance, but vetches are more vine-like. Astragalus species are used as food plants by the larvae of some Lepidoptera species including the following case-bearers of the genus Coleophora: C. astragalella (feeds exclusively on A. glycyphyllos), C. cartilaginella (feeds exclusively on Astragalus), C. colutella, C. euryaula (feeds exclusively on Astragalus), C. gallipennella (feeds exclusively on A. glycyphyllos), C. hippodromica (feeds exclusively on A. gombo), C. onobrychiella (feeds exclusively on Astragalus), C. polonicella (feeds exclusively on A. arenarius) and C. vicinella. # Medicinal use Astragalus membranaceus, or huángqí (黄芪, literally "yellow leader"; also called běiqí, 北芪, literally "northern leader") is a tonic herb originally used in Chinese medicine. It is believed to be a galactagogue, and recent studies show that it may strengthen the human immune system. The natural gum tragacanth, which is used in pharmaceuticals and textiles, is obtained from Astragalus tragacanthus. It is claimed to help the immune system, and to increase the body's resistance to common viruses. In western herbal medicine, Astragalus is primarily considered a tonic for enhancing metabolism and digestion and is consumed as a tea made from the roots of the plant. It is also traditionally used to strengthen the immune system and in the healing of wounds and injuries[1]. The biotech company Geron Corporation has determined that a molecule from Astragalus membranaceus root called TA-65 is a telomerase activator. According to PRNewswire, TA Sciences, has a license from Geron to sell TA-65 and is now selling it as a neutraceutical anti-aging product at their TA Sciences Center in New York City. [2] # Traditional use of huang qi (radix astragali) - Replenishes the Qi of the Spleen and Stomach - Causes the Yang Qi of the Spleen and Stomach to Ascend - Benefits the Qi and consolidates the surface, controls sweating - Promotes urination and disperses swelling caused by a deficiency pattern - Promotes the discharge of pus and speeds healing - Tonifies and nourishes the Qi and Blood - Used for Wasting and Thirsting syndrome (diabetes) It enters the Lung and Spleen meridians and its properties are Sweet and Slightly Warm Contraindications: Deficient Yin with Heat, Exterior Excess Heat Notes: Prepare with Honey to tonify Spleen and Stomach Qi, with wine to tonify the essence or with salt to tonify the Kidneys. # Ornamental use Several species, including A. alpinus (bluish-purple flowers), A. hypoglottis (purple flowers) and A. lotoides, are grown as ornamental plants in gardens. # External references - Astragalus - Medicinal uses of Astragalus in Armenia - Astragalus Supplements - Astralagus information de:Tragant it:Astragalus ka:გლერძი lt:Kulkšnė sv:Astragal uk:Астрагал (рід)	https://www.wikidoc.org/index.php/Astragalus
50d587bd399903be243ff7254d0a358c25468321	wikidoc	Astrognosy	Astrognosy Astrognosy deals with the materials of celestial objects and their general exterior and interior constitution. It is a technical term in English. Generally, the performance of radiation astronomy yields facts about those portions of celestial objects such as the Sun or the Earth that are radiating at least in the direction of the telescopes and detectors where the observer is at. But, what about the constitution of any celestial object with depth away from the radiating surface or near-surface region? # Sun On the right is a model for the internal structure of the Sun. # Mercury A theory for the internal structure of Mercury is shown on the right, where - Crust - 100-200 km thick, - Mantle - 600 km thick, and - Nucleus - 1,800 km radius. # Venus On the right is a model for the interior structure of Venus. # Earth Evidence from geoseismology, heat flow at the surface, and mineral physics is combined with the Earth's mass and moment of inertia to infer models of the Earth's interior - its composition, density, temperature, pressure. For example, the Earth's mean specific gravity (5.515) is far higher than the typical specific gravity of rocks at the surface (2.7–3.3), implying that the deeper material is denser. This is also implied by its low moment of inertia (0.33 M R2, compared to 0.4 M R2 for a sphere of constant density). However, some of the density increase is compression under the enormous pressures inside the Earth. The effect of pressure can be calculated using the Adams–Williamson equation. The conclusion is that pressure alone cannot account for the increase in density. Reconstruction of seismic reflections in the deep interior indicate some major discontinuities in seismic velocities that demarcate the major zones of the Earth: inner core, outer core, mantle, lithosphere and crust. The seismic model of the Earth does not by itself determine the composition of the layers. For a complete model of the Earth, mineral physics is needed to interpret seismic velocities in terms of composition. The mineral properties are temperature-dependent, so the geotherm must also be determined. This requires physical theory for thermal conduction and convection and the heat contribution of radioactive elements. The main model for the radial structure of the interior of the Earth is the Preliminary Reference Earth Model (PREM). Some parts of this model have been updated by recent findings in mineral physics (see post-perovskite) and supplemented by seismic tomography. # Shapes Data for the shape of the Earth is from the Earth2014 global relief model. Due to rotation, the Earth is flattened at the poles and bulges around the equator. The diameter of the Earth at the equator is 43 kilometres (26.718961256 mi) larger than the pole-to-pole diameter. Thus the point on the surface farthest from Earth's center of mass is the summit of the equatorial Chimborazo volcano in Ecuador. The average diameter of the reference spheroid is 12,742 kilometres (7,917.511728464 mi). Local topography deviates from this idealized spheroid, although on a global scale these deviations are small compared to Earth's radius: The maximum deviation of only 0.17% is at the Mariana Trench (10,911 metres (35,797.2441489 ft) below local sea level), whereas Mount Everest (8,848 metres (29,028.8714352 ft) above local sea level) represents a deviation of 0.14%. If Earth were shrunk to the size of a billiard ball, some areas of Earth such as large mountain ranges and oceanic trenches would feel like tiny imperfections, whereas much of the planet, including the Great Plains and the abyssal plains, would feel smoother. # Crusts Def. the "outermost layer of the lithosphere of the Earth" is called the crust. About 71% of Earth's surface is covered with water, mostly by oceans. The total surface area of Earth is about 510 (Expression error: Unexpected round operator. ). Of this, 70.8%, or 361.13 (Expression error: Missing operand for . ), is below sea level and covered by ocean water. Below the ocean's surface are much of the continental shelf, mountains, volcanoes, oceanic trenches, submarine canyons, oceanic plateaus, abyssal plains, and a globe-spanning mid-ocean ridge system. The remaining 29.2%, or 148.94 (Expression error: Missing operand for . ), not covered by water has terrain that varies greatly from place to place and consists of mountains, deserts, plains, plateaus, and other landforms. Tectonics and erosion, volcanic eruptions, flooding, weathering, glaciation, the growth of coral reefs, and meteorite impacts are among the processes that constantly reshape the Earth's surface over geological time. The fastest-moving plates are the oceanic plates, with the Cocos Plate advancing at a rate of 75 (Expression error: Missing operand for . ) and the Pacific Plate moving 52 (Expression error: Unexpected round operator. ). At the other extreme, the slowest-moving plate is the Eurasian Plate, progressing at a typical rate of 21 (Expression error: Missing operand for . ). "By analysing levels of H2O and other molecules in microscopic "melt inclusions" caught in volcanic rock samples known as komatiites, a new timeline for when seawater started getting pushed down from the surface into the mantle – the point when convection started occurring in Earth's mantle ." The "ancient water droplets been captured by the mineral olivine, found in komatiites from the Komatiite lava flow the rocks are named after – left behind by the hottest magma ever produced in Archaean Eon (4 billion to 2.5 billion years ago)." "The mechanism which caused the crust that had been altered by seawater to sink into the mantle functioned over 3.3 billion years ago. This means that a global cycle of matter, which underpins modern plate tectonics, was established within the first billion years of the Earth's existence, and the excess water in the transition zone of the mantle came from the ancient ocean on the planet's surface." "Plate tectonics constantly recycles the planet's matter, and without it the planet would look like Mars." "Our research showing that plate tectonics started 3.3 billion years ago now coincides with the period that life started on Earth. It tells us where the planet came from and how it evolved." "The komatiite was taken from the Weltevreden Formation in the Barberton greenstone belt in South Africa." "We examined a piece of melt that was 10 microns in diameter, and analysed its chemical indicators such as H2O content, chlorine and deuterium/hydrogen ratio, and found that Earth's recycling process started about 600 million years earlier than originally thought." "We found that seawater was transported deep into the mantle and then re-emerged through volcanic plumes from the core-mantle boundary." "The chemical signature of the analysed rocks matches the lithospheric mantle – the uppermost part – from the Archaean, despite coming from further down in what's known as the transition zone between the upper and lower mantle." "That komatiites were able to grab so much water from so deep underground before being shot up to the surface suggests the plate tectonics cycle was happening earlier than 2.7 billion years ago – the current accepted starting point." # Lithospheres Between the crust and the mantle is the Mohorovičić discontinuity. Seismograms from shallow-focus earthquakes had two sets of P-waves and S-waves, one that followed a direct path near the Earth's surface and the other refracted by a high-velocity medium. The Mohorovičić discontinuity is 5 (Expression error: Unexpected round operator. ) below the ocean floor, and 20 (Expression error: Unexpected round operator. ) beneath typical continental crusts, with an average depth of 35 kilometres (21.74799172 mi). Immediately above the Moho, the velocities of primary seismic waves (P-waves) are consistent with those through basalt (6.7–7.2 km/s), and below they are similar to those through peridotite or dunite (7.6–8.6 km/s). The Moho is characterized by a transition zone of up to 500 m thick. # Mantles The mantle is mainly composed of silicates, and the boundaries between layers of the mantle are consistent with phase transitions. The mantle acts as a solid for seismic waves, but under high pressures and temperatures it deforms so that over millions of years it acts like a liquid. This makes plate tectonics possible. Geodynamics is the study of the fluid flow in the mantle and core. The mantle itself is divided into the upper mantle, transition zone, lower mantle and D′′ layer. # Outer cores Reconstructions of seismic waves in the deep interior of the Earth show that there are no S-waves in the outer core. This indicates that the outer core is liquid, because liquids cannot support shear. The outer core is liquid, and the motion of this highly conductive fluid generates the Earth's field (see geodynamo). # Inner cores We know that the Earth's core is composed of an alloy of iron and other minerals. "A PKJKP traverses the inner core as a shear wave, so this is the direct evidence that the inner core is solid, because only in the solid material the shear wave can exist. In the liquid material, say water, only the compressional wave can travel through." Studying "archived data from about 20 large earthquakes, all monitored by an array of German seismic detectors back in the 1980s and '90s" has "reliably detected" a PKJKP wave in 2005, demonstrating that the inner core is solid. The inner core, however, is solid because of the enormous pressure. The inner core "is a solid ball of superhot iron and nickel alloy about 760 miles (1,220 kilometers) in diameter. ... the inner core is, at 10,800 degrees Fahrenheit (6,000 degrees Celsius), as hot as the surface of the sun." "We know the Earth's inner core is composed mostly of iron". "The metal was subjected to more than 200 billion pascals of pressure". "aterial within Earth's inner core is apparently distributed in a lopsided way ... The weakness of iron might lead crystallites in the inner core to flow and line up a certain way". "he speed at which the inner core spun apparently fluctuated over the course of approximately decades between 1961 and 2007." "As the inner core cools, crystallizing iron releases impurities, sending lighter molten material into the liquid outer core. This upwelling, combined with the Earth's rotation, drives convection, forcing the molten metal into whirling vortices. These vortices stretch and twist magnetic field lines, creating Earth’s magnetic field. Currently, the center of the field, called an axis, emerges in the Arctic Ocean west of Ellesmere Island, about 300 miles (500 kilometers) from the geographic North Pole." "In the last decade, seismic waves from earthquakes revealed the inner core looks like a navel orange, bulging slightly more on its western half. Geoscientists recently explained the asymmetry by proposing a convective loop: The inner core might be crystallizing on one half and melting on the other." "The lopsided growth of the inner core makes convection in the outer core a little bit lopsided, and that then induces the geomagnetic field to have this lopsided or eccentric character too". "Magnetic particles trapped and aligned in rocks reveal that the magnetic north pole wandered around the Western Hemisphere over the past 10,000 years, and circled the Eastern Hemisphere before that — a result mirrored by the numerical test." "The key question for interesting ideas like translational instability is, 'Can we test it?' ... What we're doing is proposing a test, and we think it's a good test because people can go out and look for eccentricity in the rock record and that will either confirm or shoot down this idea." "Within less than 100 million years, everything that has been crystallized on the west will have melted on the east" Seismic "waves appear to travel faster through the inner core from north to south than from west to east. Seismic properties also seemed to vary between the Eastern and Western hemispheres of the globe." There is a "124-mile (200-km) thick layer of dense material detected on its surface." "he inner core shifted slightly off-center, just to the east. This would put more pressure on the western side, where it would be closer to the center of the planet, and less pressure on the eastern side. The result could be a perpetually denser Western hemisphere and a continual flow of dense fluid from the east that eventually spreads out atop the entire inner core." "The inner core is basically regenerating itself. And superimposed on that is this overall cooling that makes the inner core bigger and bigger over time". "It is the first observational evidence that the inner core rotates at a variety of speeds with respect to the mantle...It also reconciles old discrepancies". "The inner core, on average, rotates eastward. At the speeds it travels, it might, on average, complete a revolution every 750 to 1,440 years. However, these speeds appear unstable, which makes it uncertain just how long it actually takes to finish a turn on its axis". # Moon The internal structure of the Moon is modeled on the right and includes a core, mantle and crust. # Mars "This artist's concept of the interior of Mars shows a hot liquid core that is about one-half the radius of the planet. The core is mostly made of iron with some possible lighter elements such as sulfur. The mantle is the darker material between the core and the thin crust." "Mars has not cooled to a completely solid iron core, rather its interior is made up of either a completely liquid iron core or a liquid outer core with a solid inner core." "Earth has an outer liquid iron core and solid inner core. This may be the case for Mars as well." "Mars is influenced by the gravitational pull of the Sun. This causes a solid body tide with a bulge toward and away from the Sun (similar in concept to the tides on Earth). However, for Mars this bulge is much smaller, less than 1 centimeter (0.4 inch). By measuring this bulge in the Mars gravity field we can determine how flexible Mars is. The size of the measured tide is large enough to indicate the core of Mars can not be solid iron but must be at least partially liquid." "The tidal bulge is a very small but detectable force on the spacecraft. It causes a drift in the tilt of the spacecraft's orbit around Mars of one-thousandth of a degree over a month." "The precession is the slow motion of the spin pole of Mars as it moves along a cone in space (similar to a spinning top). For Mars, it takes 170,000 years to complete one revolution. The precession rate indicates how much the mass of Mars is concentrated toward the center. A faster precession rate indicates a larger dense core, compared to a slower precession rate." "Our results indicate the mass change for the southern carbon dioxide ice cap is 30 to 40 percent larger than the northern ice cap, which agrees well with the predictions of the global atmosphere models of Mars." "The amount of total mass change depends on assumptions about the shape of the sublimated portion of the cap. The largest mass exchange occurs if we assume the cap change is uniform or flat over the entire cap, while the lowest mass exchange corresponds to a conically shaped cap change." # Ceres "Observations of 1 Ceres, the largest known asteroid, have revealed that the object may be a "mini planet," and may contain large amounts of pure water ice beneath its surface." "The observations by NASA's Hubble Space Telescope also show that Ceres shares characteristics of the rocky, terrestrial planets like Earth. Ceres' shape is almost round like Earth's, suggesting that the asteroid may have a "differentiated interior," with a rocky inner core and a thin, dusty outer crust." "Ceres is an embryonic planet." "Gravitational perturbations from Jupiter billions of years ago prevented Ceres from accreting more material to become a full-fledged planet." "Hubble snapped 267 images of Ceres. From those snapshots, the astronomers determined that the asteroid has a nearly round body. The diameter at its equator is wider than at its poles. Computer models show that a nearly round object like Ceres has a differentiated interior, with denser material at the core and lighter minerals near the surface. All terrestrial planets have differentiated interiors. Asteroids much smaller than Ceres have not been found to have such interiors." # Jupiter The model for the interior of Jupiter suggests the occurrence of such materials as metallic hydrogen. # Callisto The theoretical internal structure model for Callisto on the right includes rock, monoclinic ice, tetragonal ice, hexagonal ice, and cubic ice. # Europa On the right is a model for the internal structure of Europa. # Ganymede A variety of models have been suggested for the interior constitution of Ganymede. The first diagram at the right suggests ice, water, and an iron-based core. The first image at the left suggests another interior: "The cut-out reveals the interior structure of this icy moon. This structure consists of four layers based on measurements of Ganymede's gravity field and theoretical analyses using Ganymede's known mass, size and density. Ganymede's surface is rich in water ice and Voyager and Galileo images show features which are evidence of geological and tectonic disruption of the surface in the past. As with the Earth, these geological features reflect forces and processes deep within Ganymede's interior. Based on geochemical and geophysical models, scientists expected Ganymede's interior to either consist of: a) an undifferentiated mixture of rock and ice or b) a differentiated structure with a large lunar sized "core" of rock and possibly iron overlain by a deep layer of warm soft ice capped by a thin cold rigid ice crust. Galileo's measurement of Ganymede's gravity field during its first and second encounters with the huge moon have basically confirmed the differentiated model and allowed scientists to estimate the size of these layers more accurately. In addition the data strongly suggest that a dense metallic core exists at the center of the rock core. This metallic core suggests a greater degree of heating at sometime in Ganymede's past than had been proposed before and may be the source of Ganymede's magnetic field discovered by Galileo's space physics experiments." The second image at the right suggests a variety of pressure-related ices similar to the model directly above it. This "new model, based on experiments in the laboratory that simulate salty seas, shows that the ocean and ice may be stacked up in multiple layers, more like a club sandwich." "Ice comes in different forms depending on pressures. "Ice I," the least dense form of ice, is what floats in your chilled beverages. As pressures increase, ice molecules become more tightly packed and thus more dense. Because Ganymede's oceans are up to 500 miles (800 kilometers) deep, they would experience more pressure than Earth's oceans. The deepest and most dense form of ice thought to exist on Ganymede is called "Ice VI." With enough salt, liquid in Ganymede can become dense enough to sink to the very bottom of the seafloor, below Ice VI. What's more, the model shows that a strange phenomenon might occur in the uppermost liquid layer, where ice floats upward. In this scenario, cold plumes cause Ice III to form. As the ice forms, salt precipitates out. The salt then sinks down while the ice "snows" upward. Eventually, this ice would melt, resulting in a slushy layer in Ganymede's club sandwich structure." # Io A model for the internal structure of Io shown on the right includes an ultramafic mantle and an iron and iron sulfide core. # Saturn The internal structure of the gaseous giant Saturn is modeled on the right. # Titan The internal structure of Titan is modeled on the right according to the fully differentiated dense-ocean model. # Uranus Uranus has a core and a mantle as shown in the model on the right. # Neptune "The atmosphere of Neptune, similar to Uranus, consists of mainly hydrogen, methane, and helium. Below it is a liquid hydrogen layer including helium and methane. The lower layer is liquid hydrogen compounds, oxygen, and nitrogen. It is believed that the planet core comprises rock and ice. Average density, as well as the greatest proportion of core per planet size, is the greatest among the gaseous planets." # Hypotheses - The cores of each astronomical spheroidal object in orbit around the Sun has a systematically higher positive charge than the surface of the object. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.	Astrognosy Editor-In-Chief: Henry A. Hoff Astrognosy deals with the materials of celestial objects and their general exterior and interior constitution. It is a technical term in English.[1] Generally, the performance of radiation astronomy yields facts about those portions of celestial objects such as the Sun or the Earth that are radiating at least in the direction of the telescopes and detectors where the observer is at. But, what about the constitution of any celestial object with depth away from the radiating surface or near-surface region? # Sun On the right is a model for the internal structure of the Sun. # Mercury A theory for the internal structure of Mercury is shown on the right, where - Crust - 100-200 km thick, - Mantle - 600 km thick, and - Nucleus - 1,800 km radius. # Venus On the right is a model for the interior structure of Venus. # Earth Evidence from geoseismology, heat flow at the surface, and mineral physics is combined with the Earth's mass and moment of inertia to infer models of the Earth's interior - its composition, density, temperature, pressure. For example, the Earth's mean specific gravity (5.515) is far higher than the typical specific gravity of rocks at the surface (2.7–3.3), implying that the deeper material is denser. This is also implied by its low moment of inertia (0.33 M R2, compared to 0.4 M R2 for a sphere of constant density). However, some of the density increase is compression under the enormous pressures inside the Earth. The effect of pressure can be calculated using the Adams–Williamson equation. The conclusion is that pressure alone cannot account for the increase in density. Reconstruction of seismic reflections in the deep interior indicate some major discontinuities in seismic velocities that demarcate the major zones of the Earth: inner core, outer core, mantle, lithosphere and crust. The seismic model of the Earth does not by itself determine the composition of the layers. For a complete model of the Earth, mineral physics is needed to interpret seismic velocities in terms of composition. The mineral properties are temperature-dependent, so the geotherm must also be determined. This requires physical theory for thermal conduction and convection and the heat contribution of [radionuclides] radioactive elements. The main model for the radial structure of the interior of the Earth is the Preliminary Reference Earth Model (PREM). Some parts of this model have been updated by recent findings in mineral physics (see post-perovskite) and supplemented by seismic tomography. # Shapes Data for the shape of the Earth is from the Earth2014 global relief model.[2] Due to rotation, the Earth is flattened at the poles and bulges around the equator.[3] The diameter of the Earth at the equator is 43 kilometres (26.718961256 mi) larger than the pole-to-pole diameter.[4] Thus the point on the surface farthest from Earth's center of mass is the summit of the equatorial Chimborazo volcano in Ecuador.[5] [6] [7][8] The average diameter of the reference spheroid is 12,742 kilometres (7,917.511728464 mi). Local topography deviates from this idealized spheroid, although on a global scale these deviations are small compared to Earth's radius: The maximum deviation of only 0.17% is at the Mariana Trench (10,911 metres (35,797.2441489 ft) below local sea level), whereas Mount Everest (8,848 metres (29,028.8714352 ft) above local sea level) represents a deviation of 0.14%. If Earth were shrunk to the size of a billiard ball, some areas of Earth such as large mountain ranges and oceanic trenches would feel like tiny imperfections, whereas much of the planet, including the Great Plains and the abyssal plains, would feel smoother.[9] # Crusts Def. the "outermost layer of the lithosphere of the Earth"[10] is called the crust. About 71% of Earth's surface is covered with water, mostly by oceans.[11] The total surface area of Earth is about 510 (Expression error: Unexpected round operator. ).[12] Of this, 70.8%,[12] or 361.13 (Expression error: Missing operand for . ), is below sea level and covered by ocean water.[13] Below the ocean's surface are much of the continental shelf, mountains, volcanoes,[4] oceanic trenches, submarine canyons, oceanic plateaus, abyssal plains, and a globe-spanning mid-ocean ridge system. The remaining 29.2%, or 148.94 (Expression error: Missing operand for . ), not covered by water has terrain that varies greatly from place to place and consists of mountains, deserts, plains, plateaus, and other landforms. Tectonics and erosion, volcanic eruptions, flooding, weathering, glaciation, the growth of coral reefs, and meteorite impacts are among the processes that constantly reshape the Earth's surface over geological time.[14] [15] The fastest-moving plates are the oceanic plates, with the Cocos Plate advancing at a rate of 75 (Expression error: Missing operand for . )[20] and the Pacific Plate moving 52 (Expression error: Unexpected round operator. ). At the other extreme, the slowest-moving plate is the Eurasian Plate, progressing at a typical rate of 21 (Expression error: Missing operand for . ).[21] "By analysing levels of H2O and other molecules in microscopic "melt inclusions" caught in volcanic rock samples known as komatiites, [...] a new timeline for when seawater started getting pushed down from the surface into the mantle – the point when convection started occurring in Earth's mantle [has been derived]."[22] The "ancient water droplets [had] been captured by the mineral olivine, found in komatiites from the Komatiite lava flow the rocks are named after – left behind by the hottest magma ever produced in Archaean Eon (4 billion to 2.5 billion years ago)."[22] "The mechanism which caused the crust that had been altered by seawater to sink into the mantle functioned over 3.3 billion years ago. This means that a global cycle of matter, which underpins modern plate tectonics, was established within the first billion years of the Earth's existence, and the excess water in the transition zone of the mantle came from the ancient ocean on the planet's surface."[23] "Plate tectonics constantly recycles the planet's matter, and without it the planet would look like Mars."[24] "Our research showing that plate tectonics started 3.3 billion years ago now coincides with the period that life started on Earth. It tells us where the planet came from and how it evolved."[24] "The komatiite [...] was taken from the Weltevreden Formation in the Barberton greenstone belt in South Africa."[22] "We examined a piece of melt that was 10 microns [0.01 mm or three-ten-thousandths of an inch] in diameter, and analysed its chemical indicators such as H2O content, chlorine and deuterium/hydrogen ratio, and found that Earth's recycling process started about 600 million years earlier than originally thought."[24] "We found that seawater was transported deep into the mantle and then re-emerged through volcanic plumes from the core-mantle boundary."[24] "The chemical signature of the analysed rocks matches the lithospheric mantle – the uppermost part – from the Archaean, despite coming from further down in what's known as the transition zone between the upper and lower mantle."[22] "That komatiites were able to grab so much water from so deep underground before being shot up to the surface suggests the plate tectonics cycle was happening earlier than 2.7 billion years ago – the current accepted starting point."[22] # Lithospheres Between the crust and the mantle is the Mohorovičić discontinuity.[25] Seismograms from shallow-focus earthquakes had two sets of P-waves and S-waves, one that followed a direct path near the Earth's surface and the other refracted by a high-velocity medium.[26] The Mohorovičić discontinuity is 5 (Expression error: Unexpected round operator. ) below the ocean floor, and 20 (Expression error: Unexpected round operator. ) beneath typical continental crusts, with an average depth of 35 kilometres (21.74799172 mi).[27] Immediately above the Moho, the velocities of primary seismic waves (P-waves) are consistent with those through basalt (6.7–7.2 km/s), and below they are similar to those through peridotite or dunite (7.6–8.6 km/s).[28] The Moho is characterized by a transition zone of up to 500 m thick.[29] # Mantles The mantle is mainly composed of silicates, and the boundaries between layers of the mantle are consistent with phase transitions.[30] The mantle acts as a solid for seismic waves, but under high pressures and temperatures it deforms so that over millions of years it acts like a liquid. This makes plate tectonics possible. Geodynamics is the study of the fluid flow in the mantle and core. The mantle itself is divided into the upper mantle, transition zone, lower mantle and D′′ layer. # Outer cores Reconstructions of seismic waves in the deep interior of the Earth show that there are no S-waves in the outer core. This indicates that the outer core is liquid, because liquids cannot support shear. The outer core is liquid, and the motion of this highly conductive fluid generates the Earth's field (see geodynamo). # Inner cores We know that the Earth's core is composed of an alloy of iron and other minerals.[30] "A PKJKP [P wave, traversing the outer core K, and the inner core J, to emerge again as the P wave] traverses the inner core as a shear wave, so this is the direct evidence that the inner core is solid, because only in the solid material the shear wave can exist. In the liquid material, say water, only the compressional wave can travel through."[31] Studying "archived data from about 20 large earthquakes, all monitored by an array of German seismic detectors back in the 1980s and '90s" has "reliably detected" a PKJKP wave in 2005, demonstrating that the inner core is solid.[32] The inner core, however, is solid because of the enormous pressure.[25] The inner core "is a solid ball of superhot iron and nickel alloy about 760 miles (1,220 kilometers) in diameter. ... the inner core is, at 10,800 degrees Fahrenheit (6,000 degrees Celsius), as hot as the surface of the sun."[33] "We know the Earth's inner core is composed mostly of iron".[34] "The metal [iron] was subjected to more than 200 billion pascals of pressure".[33] "[M]aterial within Earth's inner core is apparently distributed in a lopsided way ... The weakness of iron might lead crystallites in the inner core to flow and line up a certain way".[33] "[T]he speed at which the inner core spun apparently fluctuated over the course of approximately decades between 1961 and 2007."[33] "As the inner core cools, crystallizing iron releases impurities, sending lighter molten material into the liquid outer core. This upwelling, combined with the Earth's rotation, drives convection, forcing the molten metal into whirling vortices. These vortices stretch and twist magnetic field lines, creating Earth’s magnetic field. Currently, the center of the field, called an axis, emerges in the Arctic Ocean west of Ellesmere Island, about 300 miles (500 kilometers) from the geographic North Pole."[35] "In the last decade, seismic waves from earthquakes revealed the inner core looks like a navel orange, bulging slightly more on its western half. Geoscientists recently explained the asymmetry by proposing a convective loop: The inner core might be crystallizing on one half and melting on the other."[35] "The lopsided growth of the inner core makes convection in the outer core a little bit lopsided, and that then induces the geomagnetic field to have this lopsided or eccentric character too".[36] "Magnetic particles trapped and aligned in rocks reveal that the magnetic north pole wandered around the Western Hemisphere over the past 10,000 years, and circled the Eastern Hemisphere before that — a result mirrored by the numerical test."[35] "The key question for interesting ideas like translational instability is, 'Can we test it?' ... What we're doing is proposing a test, and we think it's a good test because people can go out and look for eccentricity in the rock record and that will either confirm or shoot down this idea."[36] "Within less than 100 million years, everything that has been crystallized on the west will have melted on the east"[37] Seismic "waves appear to travel faster through the inner core from north to south than from west to east. Seismic properties also seemed to vary between the Eastern and Western hemispheres of the globe."[38] There is a "124-mile (200-km) thick layer of dense material detected on its surface."[38] "[T]he inner core [may be] shifted slightly off-center, just to the east. This would put more pressure on the western side, where it would be closer to the center of the planet, and less pressure on the eastern side. The result could be a perpetually denser Western hemisphere and a continual flow of dense fluid from the east that eventually spreads out atop the entire inner core."[38] "The inner core is basically regenerating itself. And superimposed on that is this overall cooling that makes the inner core bigger and bigger over time".[39] "It is the first observational evidence that the inner core rotates at a variety of speeds with respect to the mantle...It also reconciles old discrepancies".[40] "The inner core, on average, rotates eastward. At the speeds it travels, it might, on average, complete a revolution every 750 to 1,440 years. However, these speeds appear unstable, which makes it uncertain just how long it actually takes to finish a turn on its axis".[33] # Moon The internal structure of the Moon is modeled on the right and includes a core, mantle and crust. # Mars "This artist's concept of the interior of Mars [on the right] shows a hot liquid core that is about one-half the radius of the planet. The core is mostly made of iron with some possible lighter elements such as sulfur. The mantle is the darker material between the core and the thin crust."[41] "Mars has not cooled to a completely solid iron core, rather its interior is made up of either a completely liquid iron core or a liquid outer core with a solid inner core."[41] "Earth has an outer liquid iron core and solid inner core. This may be the case for Mars as well."[41] "Mars is influenced by the gravitational pull of the Sun. This causes a solid body tide with a bulge toward and away from the Sun (similar in concept to the tides on Earth). However, for Mars this bulge is much smaller, less than 1 centimeter (0.4 inch). By measuring this bulge in the Mars gravity field we can determine how flexible Mars is. The size of the measured tide is large enough to indicate the core of Mars can not be solid iron but must be at least partially liquid."[41] "The tidal bulge is a very small but detectable force on the spacecraft. It causes a drift in the tilt of the spacecraft's orbit around Mars of one-thousandth of a degree over a month."[42] "The precession is the slow motion of the spin pole of Mars as it moves along a cone in space (similar to a spinning top). For Mars, it takes 170,000 years to complete one revolution. The precession rate indicates how much the mass of Mars is concentrated toward the center. A faster precession rate indicates a larger dense core, compared to a slower precession rate."[41] "Our results indicate the mass change for the southern carbon dioxide ice cap is 30 to 40 percent larger than the northern ice cap, which agrees well with the predictions of the global atmosphere models of Mars."[41] "The amount of total mass change depends on assumptions about the shape of the sublimated portion of the cap. The largest mass exchange occurs if we assume the cap change is uniform or flat over the entire cap, while the lowest mass exchange corresponds to a conically shaped cap change."[41] # Ceres "Observations of 1 Ceres, the largest known asteroid, have revealed that the object may be a "mini planet," and may contain large amounts of pure water ice beneath its surface."[43] "The observations by NASA's Hubble Space Telescope also show that Ceres shares characteristics of the rocky, terrestrial planets like Earth. Ceres' shape is almost round like Earth's, suggesting that the asteroid may have a "differentiated interior," with a rocky inner core and a thin, dusty outer crust."[43] "Ceres is an embryonic planet."[43] "Gravitational perturbations from Jupiter billions of years ago prevented Ceres from accreting more material to become a full-fledged planet."[43] "Hubble snapped 267 images of Ceres. From those snapshots, the astronomers determined that the asteroid has a nearly round body. The diameter at its equator is wider than at its poles. Computer models show that a nearly round object like Ceres has a differentiated interior, with denser material at the core and lighter minerals near the surface. All terrestrial planets have differentiated interiors. Asteroids much smaller than Ceres have not been found to have such interiors."[43] # Jupiter The model for the interior of Jupiter suggests the occurrence of such materials as metallic hydrogen. # Callisto The theoretical internal structure model for Callisto on the right includes rock, monoclinic ice, tetragonal ice, hexagonal ice, and cubic ice. # Europa On the right is a model for the internal structure of Europa. # Ganymede A variety of models have been suggested for the interior constitution of Ganymede. The first diagram at the right suggests ice, water, and an iron-based core. The first image at the left suggests another interior: "The cut-out reveals the interior structure of this icy moon. This structure consists of four layers based on measurements of Ganymede's gravity field and theoretical analyses using Ganymede's known mass, size and density. Ganymede's surface is rich in water ice and Voyager and Galileo images show features which are evidence of geological and tectonic disruption of the surface in the past. As with the Earth, these geological features reflect forces and processes deep within Ganymede's interior. Based on geochemical and geophysical models, scientists expected Ganymede's interior to either consist of: a) an undifferentiated mixture of rock and ice or b) a differentiated structure with a large lunar sized "core" of rock and possibly iron overlain by a deep layer of warm soft ice capped by a thin cold rigid ice crust. Galileo's measurement of Ganymede's gravity field during its first and second encounters with the huge moon have basically confirmed the differentiated model and allowed scientists to estimate the size of these layers more accurately. In addition the data strongly suggest that a dense metallic core exists at the center of the rock core. This metallic core suggests a greater degree of heating at sometime in Ganymede's past than had been proposed before and may be the source of Ganymede's magnetic field discovered by Galileo's space physics experiments."[44] The second image at the right suggests a variety of pressure-related ices similar to the model directly above it. This "new model, based on experiments in the laboratory that simulate salty seas, shows that the ocean and ice may be stacked up in multiple layers, more like a club sandwich."[45] "Ice comes in different forms depending on pressures. "Ice I," the least dense form of ice, is what floats in your chilled beverages. As pressures increase, ice molecules become more tightly packed and thus more dense. Because Ganymede's oceans are up to 500 miles (800 kilometers) deep, they would experience more pressure than Earth's oceans. The deepest and most dense form of ice thought to exist on Ganymede is called "Ice VI." [...] With enough salt, liquid in Ganymede can become dense enough to sink to the very bottom of the seafloor, below Ice VI. [...] What's more, the model shows that a strange phenomenon might occur in the uppermost liquid layer, where ice floats upward. In this scenario, cold plumes cause Ice III to form. As the ice forms, salt precipitates out. The salt then sinks down while the ice "snows" upward. Eventually, this ice would melt, resulting in a slushy layer in Ganymede's club sandwich structure."[45] # Io A model for the internal structure of Io shown on the right includes an ultramafic mantle and an iron and iron sulfide core. # Saturn The internal structure of the gaseous giant Saturn is modeled on the right. # Titan The internal structure of Titan is modeled on the right according to the fully differentiated dense-ocean model. # Uranus Uranus has a core and a mantle as shown in the model on the right. # Neptune "The atmosphere of Neptune, similar to Uranus, consists of mainly hydrogen, methane, and helium. Below it is a liquid hydrogen layer including helium and methane. The lower layer is liquid hydrogen compounds, oxygen, and nitrogen. It is believed that the planet core comprises rock and ice. Average density, as well as the greatest proportion of core per planet size, is the greatest among the gaseous planets."[46] # Hypotheses - The cores of each astronomical spheroidal object in orbit around the Sun has a systematically higher positive charge than the surface of the object. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff. Initial content for this page in some instances came from Wikiversity.	https://www.wikidoc.org/index.php/Astrognosy
17aeb349bb1c638126741cb22b079fa92f8f7b0a	wikidoc	Astrovirus	Astrovirus An astrovirus is a type of virus that infects humans. They have been poorly studied due to the fact that they do not grow in culture. Astroviruses belong to the family Astroviridae along with a virus known as mamastrovirus. They were first described in the year 1975 using electron microscopes during an outbreak of diarrhoea. Astrovirus has a non-segmented, single stranded, positive sense RNA genome within a non-enveloped icosahedral capsid. # Effects Members of a relatively new virus family, the astroviridae, astroviruses are now recognised as a major cause of gastroenteritis in children and adults. They are non-enveloped viruses displaying cubic symmetry, approximately 28-30nm in diameter. The genome consists of a positive sense single strand of RNA encoding a varying array of structural proteins. A study of intestinal disease in the UK, published in 1999 determined incidence as 3.8/1000 patient years in the community (95%CI, range2.3-6.4), the fourth most common known cause of viral gastroenteritis. Studies in the USA have detected astroviruses in the stools of 2-9% of children presenting symptoms; illness is most frequent in children of less than two years, although outbreaks among adults and the elderly have been reported. Early studies carried out in Glasgow demonstrated that a significant proportion of babies excreting virus particles, 12%, did not exhibit gastrointestinal symptoms, and seroprevalence studies carried out in the US have shown that 90% of children have antibody to HastV-1 by age 9, suggesting that (largely asymptomatic) infection is common. There is, as with most viral causes of gastroenteritis, a peak of incidence in the winter. Symptoms include diarrhoea, headache, malaise and nausea, vomiting being a less common complaint, and are usually milder than those experienced with rotavirus infection, and as a result dehydration is less severe. Incubation takes 3-4 days, and symptoms persist for less than 5 days in uncomplicated cases. Diagnosis is achieved using electron microscopy; immune amplification is not necessarily required due to large numbers of virus particles in the stools. ELISAs, immunofluorescence, and nucleic acid based techniques have all been used. Treatment may not be required, rehydration using oral rehydration therapy helps maintain electrolyte balance. There is potential for development of vaccination as it appears infection proffers some short-term protection against viruses of the same serotype. # Differential diagnosis Astrovirus infection must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis. 8Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field † It could be as high as 1000 based on patient's immunity system. The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea	Astrovirus Template:ToLCleanup An astrovirus is a type of virus that infects humans. They have been poorly studied due to the fact that they do not grow in culture. Astroviruses belong to the family Astroviridae along with a virus known as mamastrovirus. They were first described in the year 1975 using electron microscopes during an outbreak of diarrhoea. Astrovirus has a non-segmented, single stranded, positive sense RNA genome within a non-enveloped icosahedral capsid. # Effects Members of a relatively new virus family, the astroviridae, astroviruses are now recognised as a major cause of gastroenteritis in children and adults. They are non-enveloped viruses displaying cubic symmetry, approximately 28-30nm in diameter. The genome consists of a positive sense single strand of RNA encoding a varying array of structural proteins. A study of intestinal disease in the UK, published in 1999 determined incidence as 3.8/1000 patient years in the community (95%CI, range2.3-6.4), the fourth most common known cause of viral gastroenteritis. Studies in the USA have detected astroviruses in the stools of 2-9% of children presenting symptoms; illness is most frequent in children of less than two years, although outbreaks among adults and the elderly have been reported. Early studies carried out in Glasgow demonstrated that a significant proportion of babies excreting virus particles, 12%, did not exhibit gastrointestinal symptoms, and seroprevalence studies carried out in the US have shown that 90% of children have antibody to HastV-1 by age 9, suggesting that (largely asymptomatic) infection is common. There is, as with most viral causes of gastroenteritis, a peak of incidence in the winter. Symptoms include diarrhoea, headache, malaise and nausea, vomiting being a less common complaint, and are usually milder than those experienced with rotavirus infection, and as a result dehydration is less severe. Incubation takes 3-4 days, and symptoms persist for less than 5 days in uncomplicated cases. Diagnosis is achieved using electron microscopy; immune amplification is not necessarily required due to large numbers of virus particles in the stools. ELISAs, immunofluorescence, and nucleic acid based techniques have all been used. Treatment may not be required, rehydration using oral rehydration therapy helps maintain electrolyte balance. There is potential for development of vaccination as it appears infection proffers some short-term protection against viruses of the same serotype. # Differential diagnosis Astrovirus infection must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis. 8Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field † It could be as high as 1000 based on patient's immunity system. The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea[1][2][3][4][4]	https://www.wikidoc.org/index.php/Astrovirus
010cda40bd3c65c115aacb11bcc81f3d941b989b	wikidoc	Nude mouse	Nude mouse A nude mouse is a genetic mutant that has a deteriorated or removed thymus gland, resulting in an inhibited immune system due to a greatly reduced number of T cells. The phenotype, or main outward appearance of the mouse is a lack of body hair, which gives it the "nude" nickname. The nude mouse is valuable to research because it can receive many different types of tissue and tumor grafts, as it mounts no rejection response. These xenografts are commonly used in research to test new methods of imaging and treating tumors. The genetic basis of the nude mouse mutation is a disruption of the FOXN1 gene . # Nomenclature The nomenclature for the nude mouse has changed several times since their discovery. Originally they were described as nu and this was updated to Hfh11nu when the mutated gene was identified as a mutation in the HNF-3/forkhead homolog 11 gene. Then in 2000 the gene responsible for the mutation was identified as a member of the Fox gene family and the nomenclature was updated to Foxn1nu. # History and significance Nude mice have been bred since at least 1937. Because it lacks a thymus, nude mice cannot generate mature T lymphocytes. Therefore they are unable to mount most types of immune responses, including: - antibody formation that requires CD4+ helper T cells - cell-mediated immune responses, which require CD4+ and/or CD8+ T cells - delayed-type hypersensitivity responses (require CD4+ T cells) - killing of virus-infected or malignant cells (requires CD8+ cytotoxic T cells) - graft rejection (requires both CD4+ and CD8+ T cells) Because of the above features, nude mice have served in the laboratory to gain insights into the immune system, leukemia, solid tumors, AIDS and other forms of immune deficiency as well as leprosy. Moreover, the absence of functioning T cells prevents nude mice from rejecting not only allografts, but they cannot even reject xenografts; that is, grafts of tissue from another species. # Genetics To create an athymic mouse, the researcher may remove genetic material from chromosome 11 which harbors the gene for Foxn1; alternatively, one could simply remove the thymus from the mouse within 24 hours of birth. Usually, the latter method is preferred as it is economically feasible and does not rely on genetic processes, including radioimmunoassays, which are often unreliable. Athymic mice are most often bred rather than produced by either of the processes mentioned above. Since nude females have underdeveloped mammary glands and are unable to effectively nurse their young, nude males are bred with heterozygous females. # Nobel Prize The concept of a "nude mouse" is the brainchild of Rosalyn Yalow. In 1977, she was awarded half the Nobel Prize for Medicine, for the development of the radioimmunoassays, mentioned above.	Nude mouse A nude mouse is a genetic mutant that has a deteriorated or removed thymus gland, resulting in an inhibited immune system due to a greatly reduced number of T cells. The phenotype, or main outward appearance of the mouse is a lack of body hair, which gives it the "nude" nickname. The nude mouse is valuable to research because it can receive many different types of tissue and tumor grafts, as it mounts no rejection response. These xenografts are commonly used in research to test new methods of imaging and treating tumors. The genetic basis of the nude mouse mutation is a disruption of the FOXN1 gene [1][2]. # Nomenclature The nomenclature for the nude mouse has changed several times since their discovery. Originally they were described as nu and this was updated to Hfh11nu when the mutated gene was identified as a mutation in the HNF-3/forkhead homolog 11 gene. Then in 2000 the gene responsible for the mutation was identified as a member of the Fox gene family and the nomenclature was updated to Foxn1nu. # History and significance Nude mice have been bred since at least 1937.[1] Because it lacks a thymus, nude mice cannot generate mature T lymphocytes. Therefore they are unable to mount most types of immune responses, including: - antibody formation that requires CD4+ helper T cells - cell-mediated immune responses, which require CD4+ and/or CD8+ T cells - delayed-type hypersensitivity responses (require CD4+ T cells) - killing of virus-infected or malignant cells (requires CD8+ cytotoxic T cells) - graft rejection (requires both CD4+ and CD8+ T cells) Because of the above features, nude mice have served in the laboratory to gain insights into the immune system, leukemia, solid tumors, AIDS and other forms of immune deficiency as well as leprosy. Moreover, the absence of functioning T cells prevents nude mice from rejecting not only allografts, but they cannot even reject xenografts; that is, grafts of tissue from another species. # Genetics To create an athymic mouse, the researcher may remove genetic material from chromosome 11 which harbors the gene for Foxn1; alternatively, one could simply remove the thymus from the mouse within 24 hours of birth. Usually, the latter method is preferred as it is economically feasible and does not rely on genetic processes, including radioimmunoassays, which are often unreliable. Athymic mice are most often bred rather than produced by either of the processes mentioned above. Since nude females have underdeveloped mammary glands and are unable to effectively nurse their young, nude males are bred with heterozygous females. # Nobel Prize The concept of a "nude mouse" is the brainchild of Rosalyn Yalow. In 1977, she was awarded half the Nobel Prize for Medicine, for the development of the radioimmunoassays, mentioned above.	https://www.wikidoc.org/index.php/Athymic_nude_mouse
992ad8ba4ee9fbe481b6d0964d3273e44dddbe64	wikidoc	Atom laser	Atom laser An atom laser is a coherent state of propagating atoms. They are created out of a Bose-Einstein condensate of atoms that are output coupled using various techniques. Much like an optical laser, an atom laser is a coherent beam that behaves like a wave. There has been some arguments that the term "atom laser" is misleading. Indeed, "laser" stands for "Light Amplification by Stimulated Emission of Radiation" which is not particularly related to the physical object called an atom laser, and if at all describes more accurately the Bose-Einstein condensate (BEC). The terminolgy most widely used in the community today is to distinguish between the BEC, typically obtained by evaporation in a concervative trap, from the atom laser itself, which is a propagative atomic wave obtained by extraction from a previously realized BEC. Some ongoing experimental research tries to obtain directly an atom laser from a "hot" beam of atomswithout making a trapped BEC first. # Introduction The first pulsed atom laser was demonstrated at MIT by Professor Wolfgang Ketterle et al in November 1996. Ketterle used an isotope of Rubidium and used an oscillating magnetic field as their output coupling technique, letting gravity pull off partial pieces looking much like a dripping tap (See movie in External Links). From the creation of the first atom laser there has been a surge in the recreation of atom lasers along with different techniques for output coupling and in general research. The current developmental stage of the atom laser is analogous to that of the optical laser during its discovery in the 1960s. To that effect the equipment and techniques are in their earliest developmental phases and still strictly in the domain of research laboratories. # Physics The physics of an atom laser is similar to that of an optical laser. The main differences between an optical and an atom laser are that atoms interact with themselves, cannot be created as photons can, and possess mass whereas photons do not (they therefore propagate at a speed below that of light). The van der Waals interaction of atoms with surfaces makes it difficult to make the atomic mirrors, typical for conventional lasers. A continuously operating (i.e. not pulsed) atom laser has not yet been built (source). There are many concepts, which differ in detail, but are basically similar. # Applications Atom lasers are critical for atom holography. Similar to conventional holography atom holography uses the diffraction of atoms. The De Broglie wavelength of the atoms is much smaller than the wavelength of light, so atom laser can create much higher resolution holographic images. Atom holography might be used to project complex integrated-circuit patterns, just a few nanometres in scale, onto semiconductors. Another application, which might also benefit from atom lasers, is atom interferometry.In an atom interferometer an atomic wave packet is coherently split into two wave packets that follow different paths before recombining. Atom interferometers, which can be more sensitive than optical interferometers, could be used to test quantum theory, and have so high precision that they may even be able to detect changes in space-time. This is because the de Broglie wavelength of the atoms is smaller than the wavelength of light, the atoms have mass, and because the internal structure of the atom can also be exploited.	Atom laser An atom laser is a coherent state of propagating atoms. They are created out of a Bose-Einstein condensate of atoms that are output coupled using various techniques. Much like an optical laser, an atom laser is a coherent beam that behaves like a wave. There has been some arguments that the term "atom laser" is misleading. Indeed, "laser" stands for "Light Amplification by Stimulated Emission of Radiation" which is not particularly related to the physical object called an atom laser, and if at all describes more accurately the Bose-Einstein condensate (BEC). The terminolgy most widely used in the community today is to distinguish between the BEC, typically obtained by evaporation in a concervative trap, from the atom laser itself, which is a propagative atomic wave obtained by extraction from a previously realized BEC. Some ongoing experimental research tries to obtain directly an atom laser from a "hot" beam of atomswithout making a trapped BEC first. # Introduction The first pulsed atom laser was demonstrated at MIT by Professor Wolfgang Ketterle et al in November 1996.[1] Ketterle used an isotope of Rubidium and used an oscillating magnetic field as their output coupling technique, letting gravity pull off partial pieces looking much like a dripping tap (See movie in External Links). From the creation of the first atom laser there has been a surge in the recreation of atom lasers along with different techniques for output coupling and in general research. The current developmental stage of the atom laser is analogous to that of the optical laser during its discovery in the 1960s. To that effect the equipment and techniques are in their earliest developmental phases and still strictly in the domain of research laboratories. # Physics The physics of an atom laser is similar to that of an optical laser. The main differences between an optical and an atom laser are that atoms interact with themselves, cannot be created as photons can, and possess mass whereas photons do not (they therefore propagate at a speed below that of light).[2] The van der Waals interaction of atoms with surfaces makes it difficult to make the atomic mirrors, typical for conventional lasers. A continuously operating (i.e. not pulsed) atom laser has not yet been built (source). There are many concepts, which differ in detail, but are basically similar. # Applications Template:Expand-section Atom lasers are critical for atom holography. Similar to conventional holography atom holography uses the diffraction of atoms. The De Broglie wavelength of the atoms is much smaller than the wavelength of light, so atom laser can create much higher resolution holographic images. Atom holography might be used to project complex integrated-circuit patterns, just a few nanometres in scale, onto semiconductors. Another application, which might also benefit from atom lasers, is atom interferometry.In an atom interferometer an atomic wave packet is coherently split into two wave packets that follow different paths before recombining. Atom interferometers, which can be more sensitive than optical interferometers, could be used to test quantum theory, and have so high precision that they may even be able to detect changes in space-time.[3] This is because the de Broglie wavelength of the atoms is smaller than the wavelength of light, the atoms have mass, and because the internal structure of the atom can also be exploited.	https://www.wikidoc.org/index.php/Atom_laser
c66dfef2e37394860d99be0057e2a450ef4f9690	wikidoc	Atovaquone	Atovaquone # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Atovaquone is an antiprotozoal that is FDA approved for the treatment of pneumocystis pneumonia. Common adverse reactions include rash, abdominal pain, diarrhea, nausea, vomiting, asthenia, headache, insomnia, cough, dyspnea, rhinitis, and fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Adults and Adolescents (13 to 16 Years): The recommended oral dose is 1,500 mg (10 mL) once daily administered with a meal. - Adults and Adolescents (13 to 16 Years): The recommended oral dose is 750 mg (5 mL) administered with meals twice daily for 21 days (total daily dose 1,500 mg). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Atovaquone in adult patients. ### Non–Guideline-Supported Use - Atovaquone 750 milligrams (mg) every 12 hours, with azithromycin 500 mg initially then 250 mg daily, each orally for 7 days. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Atovaquone in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Atovaquone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Atovaquone in pediatric patients. # Contraindications - Atovaquone Suspension is contraindicated for patients who develop or have a history of potentially life-threatening allergic reactions to any of the components of the formulation. # Warnings - Clinical experience with atovaquone for the treatment of PCP has been limited to patients with mild-to-moderate PCP (1≤45 mm Hg). Treatment of more severe episodes of PCP has not been systematically studied with this agent. Also, the efficacy of atovaquone in patients who are failing therapy with TMP-SMX has not been systematically studied. ### Precautions - Absorption of orally administered atovaquone is limited but can be significantly increased when the drug is taken with food. Plasma atovaquone concentrations have been shown to correlate with the likelihood of successful treatment and survival. Therefore, parenteral therapy with other agents should be considered for patients who have difficulty taking atovaquone with food. Gastrointestinal disorders may limit absorption of orally administered drugs. Patients with these disorders also may not achieve plasma concentrations of atovaquone associated with response to therapy in controlled trials. - Based upon the spectrum of in vitro antimicrobial activity, atovaquone is not effective therapy for concurrent pulmonary conditions such as bacterial, viral, or other fungal pneumonia or mycobacterial diseases. Clinical deterioration in patients may be due to infections with other pathogens, as well as progressive PCP. All patients with acute PCP should be carefully evaluated for other possible causes of pulmonary disease and treated with additional agents as appropriate. - Rare cases of hepatitis, elevated liver function tests and one case of fatal liver failure have been reported in patients treated with atovaquone. A causal relationship between atovaquone use and these events could not be established because of numerous confounding medical conditions and concomitant drug therapies. - If it is necessary to treat patients with severe hepatic impairment, caution is advised and administration should be closely monitored. # Adverse Reactions ## Clinical Trials Experience - Because many patients who participated in clinical trials with atovaquone had complications of advanced HIV disease, it was often difficult to distinguish adverse events caused by atovaquone from those caused by underlying medical conditions. There were no life-threatening or fatal adverse experiences caused by atovaquone. - PCP Prevention Studies: In the dapsone comparative study of Atovaquone Suspension, adverse experience data were collected only for treatment-limiting events. Among the entire population (n = 1,057), treatment-limiting events occurred at similar frequencies in patients treated with Atovaquone Suspension or dapsone (Table 6). Among patients who were taking neither dapsone nor atovaquone at enrollment (n = 487), treatment-limiting events occurred in 43% of patients treated with dapsone and 20% of patients treated with Atovaquone Suspension (P <0.001). In both populations, the type of treatment-limiting events differed between the 2 treatment arms. Hypersensitivity reactions (rash, fever, allergic reaction) and anemia were more common in patients treated with dapsone, while gastrointestinal events (nausea, diarrhea and vomiting) were more common in patients treated with Atovaquone Suspension. - Table 7 summarizes the clinical adverse experiences reported by ≥20% of patients in any group in the aerosolized pentamidine comparative study of Atovaquone Suspension (n = 549), regardless of attribution. The incidence of adverse experiences at the recommended dose was similar to that seen with aerosolized pentamidine. Rash was the only individual adverse experience that occurred significantly more commonly in patients treated with both dosages of Atovaquone Suspension (39% to 46%) than in patients treated with aerosolized pentamidine (28%). Among patients treated with Atovaquone Suspension, there was no evidence of a dose-related increase in the incidence of adverse experiences. Treatment-limiting adverse experiences occurred less often in patients treated with aerosolized pentamidine (7%) than in patients treated with 1,500 mg Atovaquone Suspension once daily (25%, P ≤0.001) or 750 mg Atovaquone Suspension once daily (16%, P = 0.004). The most common adverse experiences requiring discontinuation of dosing in the group receiving 1,500 mg Atovaquone Suspension once daily were rash (6%), diarrhea (4%) and nausea (3%). The most common adverse experience requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%). - Other events occurring in ≥10% of the patients receiving the recommended dose of atovaquone included sweating, flu syndrome, pain, sinusitis, pruritus, insomnia, depression and myalgia. Bronchospasm occurred more frequently in patients receiving aerosolized pentamidine (11%) than in patients receiving atovaquone 1,500 mg/day (4%) and atovaquone 750 mg/day (2%). - Neither atovaquone nor aerosolized pentamidine was associated with a substantial change from baseline values in any measured laboratory parameter, nor were there any significant differences in any measured laboratory parameter between atovaquone and aerosolized pentamidine. Some patients had laboratory abnormalities considered serious by the investigator or that contributed to discontinuation of therapy. - PCP Treatment Studies: Table 8 summarizes all the clinical adverse experiences reported by ≥5% of the study population during the TMP-SMX comparative study of atovaquone (n = 408), regardless of attribution. The incidence of adverse experiences with Atovaquone Suspension at the recommended dose was similar to that seen with the tablet formulation of atovaquone. - Although an equal percentage of patients receiving atovaquone and TMP-SMX reported at least 1 adverse experience, more patients receiving TMP-SMX required discontinuation of therapy due to an adverse event. Twenty-four percent of patients receiving TMP-SMX were prematurely discontinued from therapy due to an adverse experience versus 9% of patients receiving atovaquone. Four percent of patients receiving atovaquone had therapy discontinued due to development of rash. The majority of cases of rash among patients receiving atovaquone were mild and did not require the discontinuation of dosing. The only other clinical adverse experience that led to premature discontinuation of dosing of atovaquone by more than 1 patient was vomiting (<1%). The most common adverse experience requiring discontinuation of dosing in the TMP-SMX group was rash (8%). - Laboratory test abnormalities reported for ≥5% of the study population during the treatment period are summarized in Table 9. Two percent of patients treated with atovaquone and 7% of patients treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST. In general, patients treated with atovaquone developed fewer abnormalities in measures of hepatocellular function (ALT, AST, alkaline phosphatase) or amylase values than patients treated with TMP-SMX. - Table 10 summarizes the clinical adverse experiences reported by ≥5% of the primary therapy study population (n = 144) during the comparative trial of atovaquone and intravenous pentamidine, regardless of attribution. A slightly lower percentage of patients who received atovaquone reported occurrence of adverse events than did those who received pentamidine (63% vs 72%). However, only 7% of patients discontinued treatment with atovaquone due to adverse events, while 41% of patients who received pentamidine discontinued treatment for this reason (P <;&lt0.001). Of the 5 patients who discontinued therapy with atovaquone, 3 reported rash (4%). Rash was not severe in any patient. No other reason for discontinuation of atovaquone was cited more than once. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%). - Laboratory test abnormalities reported in ≥5% of patients in the pentamidine comparative study are presented in Table 11. Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 patients who received atovaquone. One patient (1%) had elevated creatinine and BUN levels and 1 patient (1%) had elevated amylase levels. Laboratory abnormalities were the sole or contributing factor in 14 patients who prematurely discontinued pentamidine therapy. In the 71 patients who received pentamidine, laboratory parameters most frequently reported as reasons for discontinuation were hypoglycemia (11%), elevated creatinine levels (6%) and leukopenia (4%). ## Postmarketing Experience - In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of atovaquone. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to atovaquone. Methemoglobinemia, thrombocytopenia. Hypersensitivity reactions including angioedema, bronchospasm, throat tightness and urticaria. Vortex keratopathy. Pancreatitis. Rare cases of hepatitis, and one case of fatal liver failure have been reported with atovaquone usage. Erythema multiforme, Stevens-Johnson syndrome and skin desquamation have been reported in patients receiving multiple drug therapy including atovaquone. Acute renal impairment. # Drug Interactions - Atovaquone is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering atovaquone concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur. The extent of plasma protein binding of atovaquone in human plasma is not affected by the presence of therapeutic concentrations of phenytoin (15 mcg/mL), nor is the binding of phenytoin affected by the presence of atovaquone. - Rifampin: Coadministration of rifampin and Atovaquone Suspension results in a significant decrease in average steady-state plasma atovaquone concentrations (see CLINICAL PHARMACOLOGY: Drug Interactions). Alternatives to rifampin should be considered during the course of PCP treatment with atovaquone. - Rifabutin, another rifamycin, is structurally similar to rifampin and may possibly have some of the same drug interactions as rifampin. No interaction trials have been conducted with atovaquone and rifabutin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human exposure. Atovaquone caused maternal toxicity in rabbits at plasma concentrations that were approximately one half the estimated human exposure. Mean fetal body lengths and weights were decreased and there were higher numbers of early resorption and post-implantation loss per dam. It is not clear whether these effects were caused by atovaquone directly or were secondary to maternal toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations. In a separate study in rats given a single 14C-radiolabelled dose, concentrations of radiocarbon in rat fetuses were 18% (middle gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. There are no adequate and well-controlled studies in pregnant women. Atovaquone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atovaquone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Atovaquone during labor and delivery. ### Nursing Mothers - It is not known whether atovaquone is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised when atovaquone is administered to a nursing woman. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma. ### Pediatric Use - Evidence of safety and effectiveness in pediatric patients has not been established. A relationship between plasma atovaquone concentrations and successful treatment of PCP has been established in adults (see Table 2). In a study of Atovaquone Suspension in 27 HIV-infected, asymptomatic infants and children between 1 month and 13 years of age, the pharmacokinetics of atovaquone were age-dependent. No drug-related treatment-limiting adverse events were observed in the pharmacokinetic study. ### Geriatic Use - Clinical studies of atovaquone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Atovaquone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Atovaquone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Atovaquone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Atovaquone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Atovaquone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Atovaquone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Atovaquone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Atovaquone in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Atovaquone in the drug label. # Pharmacology ## Mechanism of Action - Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis jiroveci has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis. ## Structure - Atovaquone is an antiprotozoal agent. The chemical name of atovaquone is trans-2--3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22H19ClO3. The compound has the following structural formula: - Atovaquone Suspension is a formulation of micro-fine particles of atovaquone. - The atovaquone particles, reduced in size to facilitate absorption, are significantly smaller than those in the previously marketed tablet formulation. Atovaquone Suspension is for oral administration and is bright yellow with a citrus flavor. Each teaspoonful (5 mL) contains 750 mg of atovaquone and the inactive ingredients benzyl alcohol, flavor (ethanol, propylene glycol, triacetin), poloxamer 188, purified water, saccharin sodium and xanthan gum. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Atovaquone in the drug label. ## Pharmacokinetics - Absorption - Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The suspension formulation provides an approximately 2-fold increase in atovaquone bioavailability in the fasting or fed state compared to the previously marketed tablet formulation. The absolute bioavailability of a 750-mg dose of Atovaquone Suspension administered under fed conditions in 9 HIV-infected (CD4 >100 cells/mm3) volunteers was 47% ± 15%. In the same study, the bioavailability of a 750-mg dose of the previously marketed tablet formulation was 23% ± 11%. - Administering atovaquone with food enhances its absorption by approximately 2 fold. In one study, 16 healthy volunteers received a single dose of 750 mg Atovaquone Suspension after an overnight fast and following a standard breakfast (23 g fat: 610 kCal). The mean (±SD) area under the concentration-time curve (AUC) values were 324 ± 115 and 801 ± 320 hr●mcg/mL under fasting and fed conditions, respectively, representing a 2.6 ± 1-fold increase. The effect of food (23 g fat: 400 kCal) on plasma atovaquone concentrations was also evaluated in a multiple-dose, randomized, crossover study in 19 HIV-infected volunteers (CD4 <200 cells/mm3) receiving daily doses of 500 mg Atovaquone Suspension. AUC was 280 ± 114 hr●mcg/mL when atovaquone was administered with food as compared to 169 ± 77 hr●mcg/mL under fasting conditions. Maximum plasma atovaquone concentration (Cmax) was 15.1 ± 6.1 and 8.8 ± 3.7 mcg/mL when atovaquone was administered with food and under fasting conditions, respectively. - Dose Proportionality - Plasma atovaquone concentrations do not increase proportionally with dose. When Atovaquone Suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily and 1,000 mg once daily, average steady-state plasma atovaquone concentrations were 11.7 ± 4.8, 12.5 ± 5.8 and 13.5 ± 5.1 mcg/mL, respectively. The corresponding Cmax concentrations were 15.1 ± 6.1, 15.3 ± 7.6 and 16.8 ± 6.4 mcg/mL. When Atovaquone Suspension was administered to 5 HIV-infected volunteers at a dose of 750 mg twice daily, the average steady-state plasma atovaquone concentration was 21 ± 4.9 mcg/mL and Cmax was 24 ± 5.7 mcg/mL. The minimum plasma atovaquone concentration (Cmin) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL. - Distribution - Following the intravenous administration of atovaquone, the volume of distribution at steady-state (Vdss) was 0.60 ± 0.17 L/kg (n = 9). Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 mcg/mL. In 3 HIV-infected children who received 750 mg atovaquone as the tablet formulation 4 times daily for 2 weeks, the cerebrospinal fluid concentrations of atovaquone were 0.04, 0.14 and 0.26 mcg/mL, representing less than 1% of the plasma concentration. - Elimination - The plasma clearance of atovaquone following intravenous (IV) administration in 9 HIV-infected volunteers was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg). The half-life of atovaquone was 62.5 ± 35.3 hours after IV administration and ranged from 67 ± 33.4 to 77.6 ± 23.1 hours across studies following administration of Atovaquone Suspension. The half-life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. In a study where 14C-labelled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite has not been identified. - Special Populations - Pediatrics - In a study of Atovaquone Suspension in 27 HIV-infected, asymptomatic infants and children between 1 month and 13 years of age, the pharmacokinetics of atovaquone were age dependent. These patients were dosed once daily with food for 12 days. The average steady-state plasma atovaquone concentrations in the 24 patients with available concentration data are shown in Table 1. - Hepatic/Renal Impairment - The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment. - Drug Interactions - Rifampin - In a study with 13 HIV-infected volunteers, the oral administration of rifampin 600 mg every 24 hours with Atovaquone Suspension 750 mg every 12 hours resulted in a 52% ± 13% decrease in the average steady-state plasma atovaquone concentration and a 37% ± 42% increase in the average steady-state plasma rifampin concentration. The half-life of atovaquone decreased from 82 ± 36 hours when administered without rifampin to 50 ± 16 hours with rifampin. - Rifabutin, another rifamycin, is structurally similar to rifampin and may possibly have some of the same drug interactions as rifampin. No interaction trials have been conducted with atovaquone and rifabutin. - Trimethoprim/Sulfamethoxazole (TMP-SMX) - The possible interaction between atovaquone and TMP-SMX was evaluated in 6 HIV-infected adult volunteers as part of a larger multiple-dose, dose-escalation and chronic dosing study of Atovaquone Suspension. In this crossover study, Atovaquone Suspension 500 mg once daily, or TMP-SMX tablets (160 mg trimethoprim and 800 mg sulfamethoxazole) twice daily, or the combination were administered with food to achieve steady-state. No difference was observed in the average steady-state plasma atovaquone concentration after coadministration with TMP-SMX. Coadministration of atovaquone with TMP-SMX resulted in a 17% and 8% decrease in average steady-state concentrations of trimethoprim and sulfamethoxazole in plasma, respectively. This effect is minor and would not be expected to produce clinically significant events. - Zidovudine - Data from 14 HIV-infected volunteers who were given atovaquone tablets 750 mg every 12 hours with zidovudine 200 mg every 8 hours showed a 24% ± 12% decrease in zidovudine apparent oral clearance, leading to a 35% ± 23% increase in plasma zidovudine AUC. The glucuronide metabolite:parent ratio decreased from a mean of 4.5 when zidovudine was administered alone to 3.1 when zidovudine was administered with atovaquone tablets. This effect is minor and would not be expected to produce clinically significant events. Zidovudine had no effect on atovaquone pharmacokinetics. - Relationship Between Plasma Atovaquone Concentration and Clinical Outcome: In a comparative study of atovaquone tablets with TMP-SMX for oral treatment of mild-to-moderate PCP (see INDICATIONS AND USAGE), where AIDS patients received 750 mg atovaquone tablets 3 times daily for 21 days, the mean steady-state atovaquone concentration was 13.9 ± 6.9 mcg/mL (n = 133). Analysis of these data established a relationship between plasma atovaquone concentration and successful treatment. This is shown in Table 2. - A dosing regimen of Atovaquone Suspension for the treatment of mild-to-moderate PCP has been selected to achieve average plasma atovaquone concentrations of approximately 20 mcg/mL, because this plasma concentration was previously shown to be well tolerated and associated with the highest treatment success rates (Table 2). In an open-label PCP treatment study with Atovaquone Suspension, dosing regimens of 1,000 mg once daily, 750 mg twice daily, 1,500 mg once daily and 1,000 mg twice daily were explored. The average steady-state plasma atovaquone concentration achieved at the 750-mg twice-daily dose given with meals was 22 ± 10.1 mcg/mL (n = 18). ## Nonclinical Toxicology - Carcinogenicity studies in rats were negative; 24-month studies in mice showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which ranged from 1.4 to 3.6 times the average steady-state plasma concentrations in humans during acute treatment of PCP. Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay and the Cultured Human Lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay. # Clinical Studies - The indication for prevention of PCP is based on the results of 2 clinical trials comparing Atovaquone Suspension to dapsone or aerosolized pentamidine in HIV-infected adult and adolescent patients at risk of PCP (CD4 count <200 cells/mm3 or a prior episode of PCP) and intolerant to TMP-SMX. - Dapsone Comparative Study: This randomized, open-label trial enrolled a total of 1,057 patients at 48 study centers. Patients were randomized to receive 1,500 mg Atovaquone Suspension once daily (n = 536) or 100 mg dapsone once daily (n = 521). Median follow-up was 24 months. Patients randomized to the dapsone arm who were seropositive for Toxoplasma gondii and had a CD4 count <100 cells/mm3 also received pyrimethamine and folinic acid. PCP event rates are shown in Table 3. There was no significant difference in mortality rates between the groups. - Aerosolized Pentamidine Comparative Study: This randomized, open-label trial enrolled a total of 549 patients at 35 study centers. Patients were randomized to receive 1,500 mg Atovaquone Suspension once daily (n = 175), 750 mg Atovaquone Suspension once daily (n = 188), or 300 mg aerosolized pentamidine once monthly (n = 186). Median follow-up was 11.3 months. The results of the PCP event rates appear in Table 3. There were no significant differences in mortality rates among the groups. - An analysis of all PCP events (intent-to-treat analysis) showed results similar to those above. - The indication for treatment of mild-to-moderate PCP is based on the results of comparative pharmacokinetic studies of the suspension and tablet formulations (see CLINICAL PHARMACOLOGY) and clinical efficacy studies of the tablet formulation which established a relationship between plasma atovaquone concentration and successful treatment. The results of a randomized, double-blind trial comparing atovaquone to TMP-SMX in AIDS patients with mild-to-moderate PCP (defined in the study protocol as an alveolar-arterial oxygen diffusion gradient 1≤45 mm Hg and PaO2≥60 mm Hg on room air) and a randomized trial comparing atovaquone to IV pentamidine isethionate in patients with mild-to-moderate PCP intolerant to trimethoprim or sulfa-antimicrobials are summarized below: - TMP-SMX Comparative Study: This double-blind, randomized trial initiated in 1990 was designed to compare the safety and efficacy of atovaquone to that of TMP-SMX for the treatment of AIDS patients with histologically confirmed PCP. Only patients with mild-to-moderate PCP were eligible for enrollment. - A total of 408 patients were enrolled into the trial at 37 study centers. Eighty-six patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 322 patients with histologically confirmed PCP, 160 were randomized to receive atovaquone and 162 to TMP-SMX. - Study participants randomized to treatment with atovaquone were to receive 750 mg atovaquone (three 250-mg tablets) 3 times daily for 21 days and those randomized to TMP-SMX were to receive 320 mg TMP plus 1,600 mg SMX 3 times daily for 21 days. - Therapy success was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. Therapy failures included lack of response, treatment discontinuation due to an adverse experience and unevaluable. - There was a significant difference (P = 0.03) in mortality rates between the treatment groups. Among the 322 patients with confirmed PCP, 13 of 160 (8%) patients treated with atovaquone and 4 of 162 (2.5%) patients receiving TMP-SMX died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all 408 randomized patients, there were 16 (8%) deaths in the arm treated with atovaquone and 7 (3.4%) deaths in the TMP-SMX arm (P = 0.051). Of the 13 patients treated with atovaquone who died, 4 died of PCP and 5 died with a combination of bacterial infections and PCP; bacterial infections did not appear to be a factor in any of the 4 deaths among TMP-SMX-treated patients. - A correlation between plasma atovaquone concentrations and death was demonstrated; in general, patients with lower plasma concentrations were more likely to die. For those patients for whom day 4 plasma atovaquone concentration data are available, 5 (63%) of the 8 patients with concentrations <5 mcg/mL died during participation in the study. However, only 1 (2%) of the 49 patients with day 4 plasma atovaquone concentrations ≥5 mcg/mL died. - Sixty-two percent of patients on atovaquone and 64% of patients on TMP-SMX were classified as protocol-defined therapy successes (Table 4). - The failure rate due to lack of response was significantly larger for patients receiving atovaquone while the failure rate due to adverse experiences was significantly larger for patients receiving TMP-SMX. - There were no significant differences in the effect of either treatment on additional indicators of response (i.e., arterial blood gas measurements, vital signs, serum LDH levels, clinical symptoms and chest radiographs). - This unblinded, randomized trial initiated in 1991 was designed to compare the safety and efficacy of atovaquone to that of pentamidine for the treatment of histologically confirmed mild or moderate PCP in AIDS patients. Approximately 80% of the patients either had a history of intolerance to trimethoprim or sulfa-antimicrobials (the primary therapy group) or were experiencing intolerance to TMP-SMX with treatment of an episode of PCP at the time of enrollment in the study (the salvage treatment group). - Patients randomized to atovaquone were to receive 750 mg atovaquone (three 250-mg tablets) 3 times daily for 21 days and those randomized to pentamidine isethionate were to receive a 3- to 4-mg/kg single IV infusion daily for 21 days. - A total of 174 patients were enrolled into the trial at 22 study centers. Thirty-nine patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 135 patients with histologically confirmed PCP, 70 were randomized to receive atovaquone and 65 to pentamidine. One hundred and ten (110) of these were in the primary therapy group and 25 were in the salvage therapy group. One patient in the primary therapy group randomized to receive pentamidine did not receive study medication. - There was no difference in mortality rates between the treatment groups. Among the 135 patients with confirmed PCP, 10 of 70 (14%) patients randomized to atovaquone and 9 of 65 (14%) patients randomized to pentamidine died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all randomized patients, there were 11 (12.5%) deaths in the arm treated with atovaquone and 12 (14%) deaths in the pentamidine arm. For those patients for whom day 4 plasma atovaquone concentrations are available, 3 of 5 (60%) patients with concentrations <5 mcg/mL died during participation in the study. However, only 2 of 21 (9%) patients with day 4 plasma concentrations ≥5 mcg/mL died. - The therapeutic outcomes for the 134 patients who received study medication in this trial are presented in Table 5. # How Supplied - Atovaquone Suspension (bright yellow, citrus flavored) containing 750 mg atovaquone in each teaspoonful (5 mL). - Bottle of 210 mL with child-resistant cap (NDC 65162-693-88). - Store at 15° to 25°C (59° to 77°F). DO NOT FREEZE. Dispense in tight container as defined in USP. ## Storage There is limited information regarding Atovaquone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Atovaquone in the drug label. # Precautions with Alcohol - Alcohol-Atovaquone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ATOVAQUONE® # Look-Alike Drug Names There is limited information regarding Atovaquone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Atovaquone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Atovaquone is an antiprotozoal that is FDA approved for the treatment of pneumocystis pneumonia. Common adverse reactions include rash, abdominal pain, diarrhea, nausea, vomiting, asthenia, headache, insomnia, cough, dyspnea, rhinitis, and fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Adults and Adolescents (13 to 16 Years): The recommended oral dose is 1,500 mg (10 mL) once daily administered with a meal. - Adults and Adolescents (13 to 16 Years): The recommended oral dose is 750 mg (5 mL) administered with meals twice daily for 21 days (total daily dose 1,500 mg). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Atovaquone in adult patients. ### Non–Guideline-Supported Use - Atovaquone 750 milligrams (mg) every 12 hours, with azithromycin 500 mg initially then 250 mg daily, each orally for 7 days. [1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Atovaquone in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Atovaquone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Atovaquone in pediatric patients. # Contraindications - Atovaquone Suspension is contraindicated for patients who develop or have a history of potentially life-threatening allergic reactions to any of the components of the formulation. # Warnings - Clinical experience with atovaquone for the treatment of PCP has been limited to patients with mild-to-moderate PCP ([(A-a)DO2]1≤45 mm Hg). Treatment of more severe episodes of PCP has not been systematically studied with this agent. Also, the efficacy of atovaquone in patients who are failing therapy with TMP-SMX has not been systematically studied. ### Precautions - Absorption of orally administered atovaquone is limited but can be significantly increased when the drug is taken with food. Plasma atovaquone concentrations have been shown to correlate with the likelihood of successful treatment and survival. Therefore, parenteral therapy with other agents should be considered for patients who have difficulty taking atovaquone with food. Gastrointestinal disorders may limit absorption of orally administered drugs. Patients with these disorders also may not achieve plasma concentrations of atovaquone associated with response to therapy in controlled trials. - Based upon the spectrum of in vitro antimicrobial activity, atovaquone is not effective therapy for concurrent pulmonary conditions such as bacterial, viral, or other fungal pneumonia or mycobacterial diseases. Clinical deterioration in patients may be due to infections with other pathogens, as well as progressive PCP. All patients with acute PCP should be carefully evaluated for other possible causes of pulmonary disease and treated with additional agents as appropriate. - Rare cases of hepatitis, elevated liver function tests and one case of fatal liver failure have been reported in patients treated with atovaquone. A causal relationship between atovaquone use and these events could not be established because of numerous confounding medical conditions and concomitant drug therapies. - If it is necessary to treat patients with severe hepatic impairment, caution is advised and administration should be closely monitored. # Adverse Reactions ## Clinical Trials Experience - Because many patients who participated in clinical trials with atovaquone had complications of advanced HIV disease, it was often difficult to distinguish adverse events caused by atovaquone from those caused by underlying medical conditions. There were no life-threatening or fatal adverse experiences caused by atovaquone. - PCP Prevention Studies: In the dapsone comparative study of Atovaquone Suspension, adverse experience data were collected only for treatment-limiting events. Among the entire population (n = 1,057), treatment-limiting events occurred at similar frequencies in patients treated with Atovaquone Suspension or dapsone (Table 6). Among patients who were taking neither dapsone nor atovaquone at enrollment (n = 487), treatment-limiting events occurred in 43% of patients treated with dapsone and 20% of patients treated with Atovaquone Suspension (P <0.001). In both populations, the type of treatment-limiting events differed between the 2 treatment arms. Hypersensitivity reactions (rash, fever, allergic reaction) and anemia were more common in patients treated with dapsone, while gastrointestinal events (nausea, diarrhea and vomiting) were more common in patients treated with Atovaquone Suspension. - Table 7 summarizes the clinical adverse experiences reported by ≥20% of patients in any group in the aerosolized pentamidine comparative study of Atovaquone Suspension (n = 549), regardless of attribution. The incidence of adverse experiences at the recommended dose was similar to that seen with aerosolized pentamidine. Rash was the only individual adverse experience that occurred significantly more commonly in patients treated with both dosages of Atovaquone Suspension (39% to 46%) than in patients treated with aerosolized pentamidine (28%). Among patients treated with Atovaquone Suspension, there was no evidence of a dose-related increase in the incidence of adverse experiences. Treatment-limiting adverse experiences occurred less often in patients treated with aerosolized pentamidine (7%) than in patients treated with 1,500 mg Atovaquone Suspension once daily (25%, P ≤0.001) or 750 mg Atovaquone Suspension once daily (16%, P = 0.004). The most common adverse experiences requiring discontinuation of dosing in the group receiving 1,500 mg Atovaquone Suspension once daily were rash (6%), diarrhea (4%) and nausea (3%). The most common adverse experience requiring discontinuation of dosing in the group receiving aerosolized pentamidine was bronchospasm (2%). - Other events occurring in ≥10% of the patients receiving the recommended dose of atovaquone included sweating, flu syndrome, pain, sinusitis, pruritus, insomnia, depression and myalgia. Bronchospasm occurred more frequently in patients receiving aerosolized pentamidine (11%) than in patients receiving atovaquone 1,500 mg/day (4%) and atovaquone 750 mg/day (2%). - Neither atovaquone nor aerosolized pentamidine was associated with a substantial change from baseline values in any measured laboratory parameter, nor were there any significant differences in any measured laboratory parameter between atovaquone and aerosolized pentamidine. Some patients had laboratory abnormalities considered serious by the investigator or that contributed to discontinuation of therapy. - PCP Treatment Studies: Table 8 summarizes all the clinical adverse experiences reported by ≥5% of the study population during the TMP-SMX comparative study of atovaquone (n = 408), regardless of attribution. The incidence of adverse experiences with Atovaquone Suspension at the recommended dose was similar to that seen with the tablet formulation of atovaquone. - Although an equal percentage of patients receiving atovaquone and TMP-SMX reported at least 1 adverse experience, more patients receiving TMP-SMX required discontinuation of therapy due to an adverse event. Twenty-four percent of patients receiving TMP-SMX were prematurely discontinued from therapy due to an adverse experience versus 9% of patients receiving atovaquone. Four percent of patients receiving atovaquone had therapy discontinued due to development of rash. The majority of cases of rash among patients receiving atovaquone were mild and did not require the discontinuation of dosing. The only other clinical adverse experience that led to premature discontinuation of dosing of atovaquone by more than 1 patient was vomiting (<1%). The most common adverse experience requiring discontinuation of dosing in the TMP-SMX group was rash (8%). - Laboratory test abnormalities reported for ≥5% of the study population during the treatment period are summarized in Table 9. Two percent of patients treated with atovaquone and 7% of patients treated with TMP-SMX had therapy prematurely discontinued due to elevations in ALT/AST. In general, patients treated with atovaquone developed fewer abnormalities in measures of hepatocellular function (ALT, AST, alkaline phosphatase) or amylase values than patients treated with TMP-SMX. - Table 10 summarizes the clinical adverse experiences reported by ≥5% of the primary therapy study population (n = 144) during the comparative trial of atovaquone and intravenous pentamidine, regardless of attribution. A slightly lower percentage of patients who received atovaquone reported occurrence of adverse events than did those who received pentamidine (63% vs 72%). However, only 7% of patients discontinued treatment with atovaquone due to adverse events, while 41% of patients who received pentamidine discontinued treatment for this reason (P <;&lt0.001). Of the 5 patients who discontinued therapy with atovaquone, 3 reported rash (4%). Rash was not severe in any patient. No other reason for discontinuation of atovaquone was cited more than once. The most frequently cited reasons for discontinuation of pentamidine therapy were hypoglycemia (11%) and vomiting (9%). - Laboratory test abnormalities reported in ≥5% of patients in the pentamidine comparative study are presented in Table 11. Laboratory abnormality was reported as the reason for discontinuation of treatment in 2 of 73 patients who received atovaquone. One patient (1%) had elevated creatinine and BUN levels and 1 patient (1%) had elevated amylase levels. Laboratory abnormalities were the sole or contributing factor in 14 patients who prematurely discontinued pentamidine therapy. In the 71 patients who received pentamidine, laboratory parameters most frequently reported as reasons for discontinuation were hypoglycemia (11%), elevated creatinine levels (6%) and leukopenia (4%). ## Postmarketing Experience - In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of atovaquone. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to atovaquone. Methemoglobinemia, thrombocytopenia. Hypersensitivity reactions including angioedema, bronchospasm, throat tightness and urticaria. Vortex keratopathy. Pancreatitis. Rare cases of hepatitis, and one case of fatal liver failure have been reported with atovaquone usage. Erythema multiforme, Stevens-Johnson syndrome and skin desquamation have been reported in patients receiving multiple drug therapy including atovaquone. Acute renal impairment. # Drug Interactions - Atovaquone is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering atovaquone concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur. The extent of plasma protein binding of atovaquone in human plasma is not affected by the presence of therapeutic concentrations of phenytoin (15 mcg/mL), nor is the binding of phenytoin affected by the presence of atovaquone. - Rifampin: Coadministration of rifampin and Atovaquone Suspension results in a significant decrease in average steady-state plasma atovaquone concentrations (see CLINICAL PHARMACOLOGY: Drug Interactions). Alternatives to rifampin should be considered during the course of PCP treatment with atovaquone. - Rifabutin, another rifamycin, is structurally similar to rifampin and may possibly have some of the same drug interactions as rifampin. No interaction trials have been conducted with atovaquone and rifabutin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Atovaquone was not teratogenic and did not cause reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human exposure. Atovaquone caused maternal toxicity in rabbits at plasma concentrations that were approximately one half the estimated human exposure. Mean fetal body lengths and weights were decreased and there were higher numbers of early resorption and post-implantation loss per dam. It is not clear whether these effects were caused by atovaquone directly or were secondary to maternal toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal plasma concentrations. In a separate study in rats given a single 14C-radiolabelled dose, concentrations of radiocarbon in rat fetuses were 18% (middle gestation) and 60% (late gestation) of concurrent maternal plasma concentrations. There are no adequate and well-controlled studies in pregnant women. Atovaquone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atovaquone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Atovaquone during labor and delivery. ### Nursing Mothers - It is not known whether atovaquone is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised when atovaquone is administered to a nursing woman. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent atovaquone concentrations in the maternal plasma. ### Pediatric Use - Evidence of safety and effectiveness in pediatric patients has not been established. A relationship between plasma atovaquone concentrations and successful treatment of PCP has been established in adults (see Table 2). In a study of Atovaquone Suspension in 27 HIV-infected, asymptomatic infants and children between 1 month and 13 years of age, the pharmacokinetics of atovaquone were age-dependent. No drug-related treatment-limiting adverse events were observed in the pharmacokinetic study. ### Geriatic Use - Clinical studies of atovaquone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Atovaquone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Atovaquone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Atovaquone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Atovaquone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Atovaquone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Atovaquone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Atovaquone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Atovaquone in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Atovaquone in the drug label. # Pharmacology ## Mechanism of Action - Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis jiroveci has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis. ## Structure - Atovaquone is an antiprotozoal agent. The chemical name of atovaquone is trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22H19ClO3. The compound has the following structural formula: - Atovaquone Suspension is a formulation of micro-fine particles of atovaquone. - The atovaquone particles, reduced in size to facilitate absorption, are significantly smaller than those in the previously marketed tablet formulation. Atovaquone Suspension is for oral administration and is bright yellow with a citrus flavor. Each teaspoonful (5 mL) contains 750 mg of atovaquone and the inactive ingredients benzyl alcohol, flavor (ethanol, propylene glycol, triacetin), poloxamer 188, purified water, saccharin sodium and xanthan gum. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Atovaquone in the drug label. ## Pharmacokinetics - Absorption - Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The suspension formulation provides an approximately 2-fold increase in atovaquone bioavailability in the fasting or fed state compared to the previously marketed tablet formulation. The absolute bioavailability of a 750-mg dose of Atovaquone Suspension administered under fed conditions in 9 HIV-infected (CD4 >100 cells/mm3) volunteers was 47% ± 15%. In the same study, the bioavailability of a 750-mg dose of the previously marketed tablet formulation was 23% ± 11%. - Administering atovaquone with food enhances its absorption by approximately 2 fold. In one study, 16 healthy volunteers received a single dose of 750 mg Atovaquone Suspension after an overnight fast and following a standard breakfast (23 g fat: 610 kCal). The mean (±SD) area under the concentration-time curve (AUC) values were 324 ± 115 and 801 ± 320 hr●mcg/mL under fasting and fed conditions, respectively, representing a 2.6 ± 1-fold increase. The effect of food (23 g fat: 400 kCal) on plasma atovaquone concentrations was also evaluated in a multiple-dose, randomized, crossover study in 19 HIV-infected volunteers (CD4 <200 cells/mm3) receiving daily doses of 500 mg Atovaquone Suspension. AUC was 280 ± 114 hr●mcg/mL when atovaquone was administered with food as compared to 169 ± 77 hr●mcg/mL under fasting conditions. Maximum plasma atovaquone concentration (Cmax) was 15.1 ± 6.1 and 8.8 ± 3.7 mcg/mL when atovaquone was administered with food and under fasting conditions, respectively. - Dose Proportionality - Plasma atovaquone concentrations do not increase proportionally with dose. When Atovaquone Suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily and 1,000 mg once daily, average steady-state plasma atovaquone concentrations were 11.7 ± 4.8, 12.5 ± 5.8 and 13.5 ± 5.1 mcg/mL, respectively. The corresponding Cmax concentrations were 15.1 ± 6.1, 15.3 ± 7.6 and 16.8 ± 6.4 mcg/mL. When Atovaquone Suspension was administered to 5 HIV-infected volunteers at a dose of 750 mg twice daily, the average steady-state plasma atovaquone concentration was 21 ± 4.9 mcg/mL and Cmax was 24 ± 5.7 mcg/mL. The minimum plasma atovaquone concentration (Cmin) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL. - Distribution - Following the intravenous administration of atovaquone, the volume of distribution at steady-state (Vdss) was 0.60 ± 0.17 L/kg (n = 9). Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 mcg/mL. In 3 HIV-infected children who received 750 mg atovaquone as the tablet formulation 4 times daily for 2 weeks, the cerebrospinal fluid concentrations of atovaquone were 0.04, 0.14 and 0.26 mcg/mL, representing less than 1% of the plasma concentration. - Elimination - The plasma clearance of atovaquone following intravenous (IV) administration in 9 HIV-infected volunteers was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg). The half-life of atovaquone was 62.5 ± 35.3 hours after IV administration and ranged from 67 ± 33.4 to 77.6 ± 23.1 hours across studies following administration of Atovaquone Suspension. The half-life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. In a study where 14C-labelled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite has not been identified. - Special Populations - Pediatrics - In a study of Atovaquone Suspension in 27 HIV-infected, asymptomatic infants and children between 1 month and 13 years of age, the pharmacokinetics of atovaquone were age dependent. These patients were dosed once daily with food for 12 days. The average steady-state plasma atovaquone concentrations in the 24 patients with available concentration data are shown in Table 1. - Hepatic/Renal Impairment - The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment. - Drug Interactions - Rifampin - In a study with 13 HIV-infected volunteers, the oral administration of rifampin 600 mg every 24 hours with Atovaquone Suspension 750 mg every 12 hours resulted in a 52% ± 13% decrease in the average steady-state plasma atovaquone concentration and a 37% ± 42% increase in the average steady-state plasma rifampin concentration. The half-life of atovaquone decreased from 82 ± 36 hours when administered without rifampin to 50 ± 16 hours with rifampin. - Rifabutin, another rifamycin, is structurally similar to rifampin and may possibly have some of the same drug interactions as rifampin. No interaction trials have been conducted with atovaquone and rifabutin. - Trimethoprim/Sulfamethoxazole (TMP-SMX) - The possible interaction between atovaquone and TMP-SMX was evaluated in 6 HIV-infected adult volunteers as part of a larger multiple-dose, dose-escalation and chronic dosing study of Atovaquone Suspension. In this crossover study, Atovaquone Suspension 500 mg once daily, or TMP-SMX tablets (160 mg trimethoprim and 800 mg sulfamethoxazole) twice daily, or the combination were administered with food to achieve steady-state. No difference was observed in the average steady-state plasma atovaquone concentration after coadministration with TMP-SMX. Coadministration of atovaquone with TMP-SMX resulted in a 17% and 8% decrease in average steady-state concentrations of trimethoprim and sulfamethoxazole in plasma, respectively. This effect is minor and would not be expected to produce clinically significant events. - Zidovudine - Data from 14 HIV-infected volunteers who were given atovaquone tablets 750 mg every 12 hours with zidovudine 200 mg every 8 hours showed a 24% ± 12% decrease in zidovudine apparent oral clearance, leading to a 35% ± 23% increase in plasma zidovudine AUC. The glucuronide metabolite:parent ratio decreased from a mean of 4.5 when zidovudine was administered alone to 3.1 when zidovudine was administered with atovaquone tablets. This effect is minor and would not be expected to produce clinically significant events. Zidovudine had no effect on atovaquone pharmacokinetics. - Relationship Between Plasma Atovaquone Concentration and Clinical Outcome: In a comparative study of atovaquone tablets with TMP-SMX for oral treatment of mild-to-moderate PCP (see INDICATIONS AND USAGE), where AIDS patients received 750 mg atovaquone tablets 3 times daily for 21 days, the mean steady-state atovaquone concentration was 13.9 ± 6.9 mcg/mL (n = 133). Analysis of these data established a relationship between plasma atovaquone concentration and successful treatment. This is shown in Table 2. - A dosing regimen of Atovaquone Suspension for the treatment of mild-to-moderate PCP has been selected to achieve average plasma atovaquone concentrations of approximately 20 mcg/mL, because this plasma concentration was previously shown to be well tolerated and associated with the highest treatment success rates (Table 2). In an open-label PCP treatment study with Atovaquone Suspension, dosing regimens of 1,000 mg once daily, 750 mg twice daily, 1,500 mg once daily and 1,000 mg twice daily were explored. The average steady-state plasma atovaquone concentration achieved at the 750-mg twice-daily dose given with meals was 22 ± 10.1 mcg/mL (n = 18). ## Nonclinical Toxicology - Carcinogenicity studies in rats were negative; 24-month studies in mice showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which ranged from 1.4 to 3.6 times the average steady-state plasma concentrations in humans during acute treatment of PCP. Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay and the Cultured Human Lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay. # Clinical Studies - The indication for prevention of PCP is based on the results of 2 clinical trials comparing Atovaquone Suspension to dapsone or aerosolized pentamidine in HIV-infected adult and adolescent patients at risk of PCP (CD4 count <200 cells/mm3 or a prior episode of PCP) and intolerant to TMP-SMX. - Dapsone Comparative Study: This randomized, open-label trial enrolled a total of 1,057 patients at 48 study centers. Patients were randomized to receive 1,500 mg Atovaquone Suspension once daily (n = 536) or 100 mg dapsone once daily (n = 521). Median follow-up was 24 months. Patients randomized to the dapsone arm who were seropositive for Toxoplasma gondii and had a CD4 count <100 cells/mm3 also received pyrimethamine and folinic acid. PCP event rates are shown in Table 3. There was no significant difference in mortality rates between the groups. - Aerosolized Pentamidine Comparative Study: This randomized, open-label trial enrolled a total of 549 patients at 35 study centers. Patients were randomized to receive 1,500 mg Atovaquone Suspension once daily (n = 175), 750 mg Atovaquone Suspension once daily (n = 188), or 300 mg aerosolized pentamidine once monthly (n = 186). Median follow-up was 11.3 months. The results of the PCP event rates appear in Table 3. There were no significant differences in mortality rates among the groups. - An analysis of all PCP events (intent-to-treat analysis) showed results similar to those above. - The indication for treatment of mild-to-moderate PCP is based on the results of comparative pharmacokinetic studies of the suspension and tablet formulations (see CLINICAL PHARMACOLOGY) and clinical efficacy studies of the tablet formulation which established a relationship between plasma atovaquone concentration and successful treatment. The results of a randomized, double-blind trial comparing atovaquone to TMP-SMX in AIDS patients with mild-to-moderate PCP (defined in the study protocol as an alveolar-arterial oxygen diffusion gradient [(A-a)DO2]1≤45 mm Hg and PaO2≥60 mm Hg on room air) and a randomized trial comparing atovaquone to IV pentamidine isethionate in patients with mild-to-moderate PCP intolerant to trimethoprim or sulfa-antimicrobials are summarized below: - TMP-SMX Comparative Study: This double-blind, randomized trial initiated in 1990 was designed to compare the safety and efficacy of atovaquone to that of TMP-SMX for the treatment of AIDS patients with histologically confirmed PCP. Only patients with mild-to-moderate PCP were eligible for enrollment. - A total of 408 patients were enrolled into the trial at 37 study centers. Eighty-six patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 322 patients with histologically confirmed PCP, 160 were randomized to receive atovaquone and 162 to TMP-SMX. - Study participants randomized to treatment with atovaquone were to receive 750 mg atovaquone (three 250-mg tablets) 3 times daily for 21 days and those randomized to TMP-SMX were to receive 320 mg TMP plus 1,600 mg SMX 3 times daily for 21 days. - Therapy success was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. Therapy failures included lack of response, treatment discontinuation due to an adverse experience and unevaluable. - There was a significant difference (P = 0.03) in mortality rates between the treatment groups. Among the 322 patients with confirmed PCP, 13 of 160 (8%) patients treated with atovaquone and 4 of 162 (2.5%) patients receiving TMP-SMX died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all 408 randomized patients, there were 16 (8%) deaths in the arm treated with atovaquone and 7 (3.4%) deaths in the TMP-SMX arm (P = 0.051). Of the 13 patients treated with atovaquone who died, 4 died of PCP and 5 died with a combination of bacterial infections and PCP; bacterial infections did not appear to be a factor in any of the 4 deaths among TMP-SMX-treated patients. - A correlation between plasma atovaquone concentrations and death was demonstrated; in general, patients with lower plasma concentrations were more likely to die. For those patients for whom day 4 plasma atovaquone concentration data are available, 5 (63%) of the 8 patients with concentrations <5 mcg/mL died during participation in the study. However, only 1 (2%) of the 49 patients with day 4 plasma atovaquone concentrations ≥5 mcg/mL died. - Sixty-two percent of patients on atovaquone and 64% of patients on TMP-SMX were classified as protocol-defined therapy successes (Table 4). - The failure rate due to lack of response was significantly larger for patients receiving atovaquone while the failure rate due to adverse experiences was significantly larger for patients receiving TMP-SMX. - There were no significant differences in the effect of either treatment on additional indicators of response (i.e., arterial blood gas measurements, vital signs, serum LDH levels, clinical symptoms and chest radiographs). - This unblinded, randomized trial initiated in 1991 was designed to compare the safety and efficacy of atovaquone to that of pentamidine for the treatment of histologically confirmed mild or moderate PCP in AIDS patients. Approximately 80% of the patients either had a history of intolerance to trimethoprim or sulfa-antimicrobials (the primary therapy group) or were experiencing intolerance to TMP-SMX with treatment of an episode of PCP at the time of enrollment in the study (the salvage treatment group). - Patients randomized to atovaquone were to receive 750 mg atovaquone (three 250-mg tablets) 3 times daily for 21 days and those randomized to pentamidine isethionate were to receive a 3- to 4-mg/kg single IV infusion daily for 21 days. - A total of 174 patients were enrolled into the trial at 22 study centers. Thirty-nine patients without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 135 patients with histologically confirmed PCP, 70 were randomized to receive atovaquone and 65 to pentamidine. One hundred and ten (110) of these were in the primary therapy group and 25 were in the salvage therapy group. One patient in the primary therapy group randomized to receive pentamidine did not receive study medication. - There was no difference in mortality rates between the treatment groups. Among the 135 patients with confirmed PCP, 10 of 70 (14%) patients randomized to atovaquone and 9 of 65 (14%) patients randomized to pentamidine died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all randomized patients, there were 11 (12.5%) deaths in the arm treated with atovaquone and 12 (14%) deaths in the pentamidine arm. For those patients for whom day 4 plasma atovaquone concentrations are available, 3 of 5 (60%) patients with concentrations <5 mcg/mL died during participation in the study. However, only 2 of 21 (9%) patients with day 4 plasma concentrations ≥5 mcg/mL died. - The therapeutic outcomes for the 134 patients who received study medication in this trial are presented in Table 5. # How Supplied - Atovaquone Suspension (bright yellow, citrus flavored) containing 750 mg atovaquone in each teaspoonful (5 mL). - Bottle of 210 mL with child-resistant cap (NDC 65162-693-88). - Store at 15° to 25°C (59° to 77°F). DO NOT FREEZE. Dispense in tight container as defined in USP. ## Storage There is limited information regarding Atovaquone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Atovaquone in the drug label. # Precautions with Alcohol - Alcohol-Atovaquone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ATOVAQUONE®[2] # Look-Alike Drug Names There is limited information regarding Atovaquone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Atovaquone
622dc513f0e7475cb9cca0d2d7ffccb3eebb1d4c	wikidoc	Atracurium	Atracurium - Induction of neuromuscular blockade, adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation: - Initial - 0.4 to 0.5 mg/kg IV bolus - Induction of neuromuscular blockade, adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation - Maintenance - 0.08 to 0.1 mg/kg IV bolus 20 to 45 min after initial dose, then every 15 to 25 min as needed - 5 to 9 mcg/kg/min (range 2 to 15 mcg/kg/min) continuous IV infusion after initial dose, upon early evidence of spontaneous recovery; in ICU, 11 to 13 mcg/kg/min (range 4.5 to 29.5 mcg/kg/min) continuous IV infusion - Induction of neuromuscular blockade, Adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation, under halothane anesthesia, - Initial, 0.3 to 0.4 mg/kg IV - Induction of neuromuscular blockade, Adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation - Initial, 0.4 to 0.5 mg/kg IV bolus - Induction of neuromuscular blockade, Adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation - Maintenance, 0.08 to 0.1 mg/kg IV bolus 20 to 45 min after initial dose, then every 15 to 25 min as needed; children may require maintenance doses more frequently than adults - Induction of neuromuscular blockade, Adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation - Maintenance, 5 to 9 mcg/kg/min (range 2 to 15 mcg/kg/min) continuous IV infusion after initial dose, upon early evidence of spontaneous recovery - Do not give atracurium besylate by intramuscular administration. - Atracurium has no known effect on consciousness, pain threshold, or cerebration. It should be used only with adequate anesthesia. - Atracurium besylate injection, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle. Depending on the resultant pH of such mixtures, atracurium may be inactivated and a free acid may be precipitated. - Atracurium besylate injection 10 mL multiple dose vials contain benzyl alcohol. In neonates, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal. Atracurium besylate 5 mL single use vials do not contain benzyl alcohol (see Precautions: Pediatric Use). - Severe anaphylactic reactions to neuromuscular blocking agents, including atracurium besylate, have been reported. These reactions have in some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported in this class of drugs. - Table 1 includes all adverse reaction reported attributable to atracurium during clinical trials with 875 patients. - Most adverse reactions were of little clinical significance unless they were associated with significant hemodynamic changes. Table 2 summarizes the incidences of substantial vital sign changes noted during atracurium clinical trials with 530 patients, without cardiovascular disease, in whom these parameters were assessed. - Based on initial clinical practice experience in approximately 3 million patients who received atracurium in the U.S. and in the United Kingdom, spontaneously reported adverse reactions were uncommon (approximately 0.01% to 0.02%). The following adverse reactions are among the most frequently reported, but there are insufficient data to support an estimate of their incidence: - Allergic reactions (anaphylactic or anaphylactoid responses) which, in rare instances, were severe (e.g., cardiac arrest) - Inadequate block, prolonged block - Hypotension, vasodilatation (flushing), tachycardia, bradycardia - Dyspnea, bronchospasm, laryngospasm - Rash, urticaria, reaction at injection site - There have been rare spontaneous reports of seizures in ICU patients following long-term infusion of atracurium to support mechanical ventilation. There are insufficient data to define the contribution, if any, of atracurium and/or its metabolite laudanosine. (See PRECAUTIONS: Long-Term Use in Intensive Care Unit ). - There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including atracurium besylate. These reactions, in some cases, have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see Warnings and Precautions). - If other muscle relaxants are used during the same procedure, the possibility of a synergistic or antagonist effect should be considered. - The prior administration of succinylcholine does not enhance the duration, but quickens the onset and may increase the depth, of neuromuscular block induced by atracurium besylate. Atracurium should not be administered until a patient has recovered from succinylcholine-induced neuromuscular block. - Atracurium besylate was administered subcutaneously on days 6 through 18 of gestation to nonventilated Dutch rabbits. Treatment groups were given either 0.15 mg/kg once daily or 0.10 mg/kg twice daily. Lethal respiratory distress occurred in two 0.15 mg/kg animals and in one 0.10 mg/kg animal, with transient respiratory distress or other evidence of neuromuscular block occurring in 10 of 19 and in 4 of 20 of the 0.15 mg/kg and 0.10 mg/kg animals, respectively. There was an increased incidence of certain spontaneously occurring visceral and skeletal anomalies or variations in one or both treated groups when compared to non-treated controls. The percentage of male fetuses was lower (41% vs. 51%) and the post-implantation losses were increased (15% vs. 8%) in the group given 0.15 mg/kg once daily when compared to the controls; the mean numbers of implants (6.5 vs. 4.4) and normal live fetuses (5.4 vs. 3.8) were greater in this group when compared to the control group. - Atracurium besylate (0.3 mg/kg) has been administered to 26 pregnant women during delivery by cesarean section. No harmful effects were attributable to atracurium in any of the neonates, although small amounts of atracurium were shown to cross the placental barrier. The possibility of respiratory depression in the neonate should always be considered following cesarean section during which a neuromuscular blocking agent has been administered. In patients receiving magnesium sulfate, the reversal of neuromuscular block may be unsatisfactory and the dose of atracurium besylate should be lowered as indicated. - Atracurium besylate should be administered intravenously. Do not give atracurium besylate by intramuscular administration. Intramuscular administration of atracurium besylate may result in tissue irritation and there are no clinical data to support this route of administration. - As with other neuromuscular blocking agents, the use of a peripheral nerve stimulator will permit the most advantageous use of atracurium besylate, minimizing the possibility of overdosage or underdosage, and assist in the evaluation of recovery. - An atracurium besylate dose of 0.4 to 0.5 mg/kg (1.7 to 2.2 times the ED95), given as an intravenous bolus injection, is the recommended initial dose for most patients. With this dose, good or excellent conditions for nonemergency intubation can be expected in 2 to 2.5 minutes in most patients, with maximum neuromuscular block achieved approximately 3 to 5 minutes after injection. Clinically required neuromuscular block generally lasts 20 to 35 minutes under balanced anesthesia. Under balanced anesthesia, recovery to 25% of control is achieved approximately 35 to 45 minutes after injection, and recovery is usually 95% complete approximately 60 minutes after injection. - Atracurium is potentiated by isoflurane or enflurane anesthesia. The same initial atracurium besylate dose of 0.4 to 0.5 mg/kg may be used for intubation prior to administration of these inhalation agents; however, if atracurium is first administered under steady-state of isoflurane or enflurane, the initial atracurium besylate dose should be reduced by approximately one-third, i.e., to 0.25 to 0.35 mg/kg, to adjust for the potentiating effects of these anesthetic agents. With halothane, which has only a marginal (approximately 20%) potentiating effect on atracurium, smaller dosage reductions may be considered. - Atracurium besylate doses of 0.08 to 0.10 mg/kg are recommended for maintenance of neuromuscular block during prolonged surgical procedures. - The first maintenance dose will generally be required 20 to 45 minutes after the initial atracurium besylate injection, but the need for maintenance doses should be determined by clinical criteria. Because atracurium lacks cumulative effects, maintenance doses may be administered at relatively regular intervals for each patient, ranging approximately from 15 to 25 minutes under balanced anesthesia, slightly longer under isoflurane or enflurane. Higher atracurium doses (up to 0.2 mg/kg) permit maintenance dosing at longer intervals. - No atracurium dosage adjustments are required for pediatric patients two years of age or older. An atracurium besylate dose of 0.3 to 0.4 mg/kg is recommended as the initial dose for infants (1 month to 2 years of age) under halothane anesthesia. Maintenance doses may be required with slightly greater frequency in infants and children than in adults. - An initial atracurium besylate dose of 0.3 to 0.4 mg/kg, given slowly or in divided doses over one minute, is recommended for adults, children, or infants with significant cardiovascular disease and for adults, children, or infants with any history (e.g., severe anaphylactoid reactions or asthma) suggesting a greater risk of histamine release. - Dosage reductions must be considered also in patients with neuromuscular disease, severe electrolyte disorders, or carcinomatosis in which potentiation of neuromuscular block or difficulties with reversal have been demonstrated. There has been no clinical experience with atracurium in these patients, and no specific dosage adjustments can be recommended. No atracurium dosage adjustments are required for patients with renal disease. - An initial atracurium besylate dose of 0.3 to 0.4 mg/kg is recommended for adults following the use of succinylcholine for intubation under balanced anesthesia. Further reductions may be desirable with the use of potent inhalation anesthetics. The patient should be permitted to recover from the effects of succinylcholine prior to atracurium administration. Insufficient data are available for recommendation of a specific initial atracurium dose for administration following the use of succinylcholine in children and infants. - After administration of a recommended initial bolus dose of atracurium besylate injection (0.3 to 0.5 mg/kg), a diluted solution of atracurium besylate can be administered by continuous infusion to adults and pediatric patients aged 2 or more years for maintenance of neuromuscular block during extended surgical procedures. - Infusion of atracurium should be individualized for each patient. The rate of administration should be adjusted according to the patient’s response as determined by peripheral nerve stimulation. Accurate dosing is best achieved using a precision infusion device. - Infusion of atracurium should be initiated only after early evidence of spontaneous recovery from the bolus dose. An initial infusion rate of 9 to 10 mcg/kg/min may be required to rapidly counteract the spontaneous recovery of neuromuscular function. Thereafter, a rate of 5 to 9 mcg/kg/min should be adequate to maintain continuous neuromuscular block in the range of 89% to 99% in most pediatric and adult patients under balanced anesthesia. Occasional patients may require infusion rates as low as 2 mcg/kg/min or as high as 15 mcg/kg/min. - The neuromuscular blocking effect of atracurium administered by infusion is potentiated by enflurane or isoflurane and, to a lesser extent, by halothane. Reduction in the infusion rate of atracurium should, therefore, be considered for patients receiving inhalation anesthesia. The rate of atracurium infusion should be reduced by approximately one-third in the presence of steady-state enflurane or isoflurane anesthesia; smaller reductions should be considered in the presence of halothane. - In patients undergoing cardiopulmonary bypass with induced hypothermia, the rate of infusion of atracurium required to maintain adequate surgical relaxation during hypothermia (25° to 28°C) has been shown to be approximately half the rate required during normothermia. - Spontaneous recovery from neuromuscular block following discontinuation of atracurium infusion may be expected to proceed at a rate comparable to that following administration of a single bolus dose. - The principles for infusion of atracurium in the OR are also applicable to use in the ICU. - An infusion rate of 11 to 13 mcg/kg/min (range: 4.5 to 29.5) should provide adequate neuromuscular block in adult patients in an ICU. Limited information suggests that infusion rates required for pediatric patients in the ICU may be higher than in adult patients. There may be wide interpatient variability in dosage requirements and these requirements may increase or decrease with time (see PRECAUTIONS: Long-Term Use in Intensive Care Unit ). Following recovery from neuromuscular block, readministration of a bolus dose may be necessary to quickly reestablish neuromuscular block prior to reinstitution of the infusion. - The amount of infusion solution required per minute will depend upon the concentration of atracurium in the infusion solution, the desired dose of atracurium, and the patient’s weight. The following tables provide guidelines for delivery, in mL/hr (equivalent to microdrops/min when 60 microdrops = 1 mL), of atracurium solutions in concentrations of 0.2 mg/mL (20 mg in 100 mL) or 0.5 mg/mL (50 mg in 100 mL) with an infusion pump or a gravity flow device. - Atracurium besylate infusion solutions may be prepared by admixing atracurium besylate injection with an appropriate diluent such as 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection. Infusion solutions should be used within 24 hours of preparation. Unused solutions should be discarded. Solutions containing 0.2 mg/mL or 0.5 mg/mL atracurium besylate in the above diluents may be stored either under refrigeration or at room temperature for 24 hours without significant loss of potency. Care should be taken during admixture to prevent inadvertent contamination. Visually inspect prior to administration. - Spontaneous degradation of atracurium besylate has been demonstrated to occur more rapidly in Lactated Ringer’s solution than in 0.9% sodium chloride solution. Therefore, it is recommended that Lactated Ringer’s Injection not be used as a diluent in preparing solutions of atracurium besylate injection for infusion. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - Three pediatric patients (3 weeks, 4 and 5 months of age) unintentionally received doses of 0.8 mg/kg to 1 mg/kg of atracurium besylate. The time to 25% recovery (50 to 55 minutes) following these doses, which were 5 to 6 times the ED95 dose, was moderately longer than the corresponding time observed following doses 2 to 2.5 times the atracurium ED95 dose in infants (22 to 36 minutes). Cardiovascular changes were minimal. Nonetheless the possibility of cardiovascular changes must be considered in the case of overdose. - An adult patient (17 years of age) unintentionally received an initial dose of 1.3 mg/kg of atracurium besylate. The time from injection to 25% recovery (83 minutes) was approximately twice that observed following maximum recommended doses in adults (35 to 45 minutes). The patient experienced moderate hemodynamic changes (13% increase in mean arterial pressure and 27% increase in heart rate) which persisted for 40 minutes and did not require treatment. - The intravenous LD50s determined in non-ventilated male and female albino mice and male Wistar rats were 1.9, 2.01 and 1.31 mg/kg, respectively. Deaths occurred within 2 minutes and were caused by respiratory paralysis. The subcutaneous LD50 determined in non-ventilated male Wistar rats was 282.8 mg/kg. Tremors, ptosis, loss of reflexes and respiratory failure preceded death which occurred 45 to 120 minutes after injection. - Atracurium besylate is a complex molecule containing four sites at which different stereochemical configurations can occur. The symmetry of the molecule, however, results in only ten, instead of sixteen, possible different isomers. The manufacture of atracurium besylate results in these isomers being produced in unequal amounts but with a consistent ratio. Those molecules in which the methyl group attached to the quaternary nitrogen projects on the opposite side to the adjacent substituted-benzyl moiety predominate by approximately 3:1. - Atracurium Besylate Injection USP is a sterile, non-pyrogenic aqueous solution. Each mL contains 10 mg atracurium besylate. The pH is adjusted to 3.00 to 3.65 with benzenesulfonic acid. The multiple dose vial contains 0.9% benzyl alcohol added as a preservative. Atracurium besylate injection slowly loses potency with time at the rate of approximately 6% per year under refrigeration (5°C). Atracurium besylate injection should be refrigerated at 2°C to 8°C (36°F to 46°F) to preserve potency. Rate of loss in potency increases to approximately 5% per month at 25°C (77°F). Upon removal from refrigeration to room temperature storage conditions (25°C / 77°F), use atracurium besylate injection within 14 days even if rerefrigerated. - The duration of neuromuscular block produced by atracurium is approximately one-third to one-half the duration of block by d-tubocurarine, metocurine, and pancuronium at initially equipotent doses. As with other nondepolarizing neuromuscular blockers, the time to onset of paralysis decreases and the duration of maximum effect increases with increasing atracurium doses. - The ED95 (dose required to produce 95% suppression of the muscle twitch response with balanced anesthesia) has averaged 0.23 mg/kg (0.11 to 0.26 mg/kg in various studies). An initial atracurium dose of 0.4 to 0.5 mg/kg generally produces maximum neuromuscular block within 3 to 5 minutes of injection, with good or excellent intubation conditions within 2 to 2.5 minutes in most patients. Recovery from neuromuscular block (under balanced anesthesia) can be expected to begin approximately 20 to 35 minutes after injection. Under balanced anesthesia, recovery to 25% of control is achieved approximately 35 to 45 minutes after injection, and recovery is usually 95% complete approximately 60 to 70 minutes after injection. The neuromuscular blocking action of atracurium is enhanced in the presence of potent inhalation anesthetics. Isoflurane and enflurane increase the potency of atracurium and prolong neuromuscular block by approximately 35%; however, halothane’s potentiating effect (approximately 20%) is marginal (see Dosage and administration). - Repeated administration of maintenance doses of atracurium has no cumulative effect on the duration of neuromuscular block if recovery is allowed to begin prior to repeat dosing. Moreover, the time needed to recover from repeat doses does not change with additional doses. Repeat doses can therefore be administered at relatively regular intervals with predictable results. After an initial dose of 0.4 to 0.5 mg/kg under balanced anesthesia, the first maintenance dose (suggested maintenance dose is 0.08 to 0.10 mg/kg) is generally required within 20 to 45 minutes, and subsequent maintenance doses are usually required at approximately 15 to 25 minute intervals. - Once recovery from atracurium’s neuromuscular blocking effects begins, it proceeds more rapidly than recovery from d-tubocurarine, metocurine, and pancuronium. Regardless of the atracurium dose, the time from start of recovery (from complete block) to complete (95%) recovery is approximately 30 minutes under balanced anesthesia, and approximately 40 minutes under halothane, enflurane or isoflurane. Repeated doses have no cumulative effect on recovery rate. - Reversal of neuromuscular block produced by atracurium can be achieved with an anti-cholinesterase agent such as neostigmine, edrophonium, or pyridostigmine, in conjunction with an anticholinergic agent such as atropine or glycopyrrolate. Under balanced anesthesia, reversal can usually be attempted approximately 20 to 35 minutes after an initial atracurium besylate dose of 0.4 to 0.5 mg/kg, or approximately 10 to 30 minutes after a 0.08 to 0.10 mg/kg maintenance dose, when recovery of muscle twitch has started. Complete reversal is usually attained within 8 to 10 minutes of the administration of reversing agents. Rare instances of breathing difficulties, possibly related to incomplete reversal, have been reported following attempted pharmacologic antagonism of atracurium-induced neuromuscular block. As with other agents in this class, the tendency for residual neuromuscular block is increased if reversal is attempted at deep levels of block or if inadequate doses of reversal agents are employed. - The pharmacokinetics of atracurium in humans are essentially linear within the 0.3 to 0.6 mg/kg dose range. The elimination half-life is approximately 20 minutes. The duration of neuromuscular block produced by atracurium besylate does not correlate with plasma pseudocholinesterase levels and is not altered by the absence of renal function. This is consistent with the results of in vitro studies which have shown that atracurium is inactivated in plasma via two nonoxidative pathways: ester hydrolysis, catalyzed by nonspecific esterases; and Hofmann elimination, a nonenzymatic chemical process which occurs at physiological pH. Some placental transfer occurs in humans. - Radiolabel studies demonstrated that atracurium undergoes extensive degradation in cats, and that neither kidney nor liver plays a major role in this elimination. Biliary and urinary excretion were the major routes of excretion of radioactivity (totaling >90% of the labeled dose within 7 hours of dosing), of which atracurium represented only a minor fraction. The metabolites in bile and urine were similar, including products of Hofmann elimination and ester hydrolysis. - Elderly patients may have slightly altered pharmacokinetic parameters compared to younger patients, with a slightly decreased total plasma clearance which is offset by a corresponding increase in volume of distribution. The net effect is that there has been no significant difference in clinical duration and recovery from neuromuscular block observed between elderly and younger patients receiving atracurium besylate. - Atracurium is a less potent histamine releaser than d-tubocurarine or metocurine. Histamine release is minimal with initial atracurium besylate doses up to 0.5 mg/kg, and hemodynamic changes are minimal within the recommended dose range. A moderate histamine release and significant falls in blood pressure have been seen following 0.6 mg/kg of atracurium besylate. The histamine and hemodynamic responses were poorly correlated. The effects were generally short-lived and manageable, but the possibility of substantial histamine release in sensitive individuals or in patients in whom substantial histamine release would be especially hazardous (e.g., patients with significant cardiovascular disease) must be considered. - It is not known whether the prior use of other nondepolarizing neuromuscular blocking agents has any effect on the activity of atracurium. The prior use of succinylcholine decreases by approximately 2 to 3 minutes the time to maximum block induced by atracurium besylate, and may increase the depth of block. Atracurium should be administered only after a patient recovers from succinylcholine-induced neuromuscular block.	Atracurium - Induction of neuromuscular blockade, adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation: - Initial - 0.4 to 0.5 mg/kg IV bolus - Induction of neuromuscular blockade, adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation - Maintenance - 0.08 to 0.1 mg/kg IV bolus 20 to 45 min after initial dose, then every 15 to 25 min as needed - 5 to 9 mcg/kg/min (range 2 to 15 mcg/kg/min) continuous IV infusion after initial dose, upon early evidence of spontaneous recovery; in ICU, 11 to 13 mcg/kg/min (range 4.5 to 29.5 mcg/kg/min) continuous IV infusion - Induction of neuromuscular blockade, Adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation, under halothane anesthesia, - Initial, 0.3 to 0.4 mg/kg IV - Induction of neuromuscular blockade, Adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation - Initial, 0.4 to 0.5 mg/kg IV bolus - Induction of neuromuscular blockade, Adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation - Maintenance, 0.08 to 0.1 mg/kg IV bolus 20 to 45 min after initial dose, then every 15 to 25 min as needed; children may require maintenance doses more frequently than adults - Induction of neuromuscular blockade, Adjunct to general anesthesia, to facilitate endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation - Maintenance, 5 to 9 mcg/kg/min (range 2 to 15 mcg/kg/min) continuous IV infusion after initial dose, upon early evidence of spontaneous recovery - Do not give atracurium besylate by intramuscular administration. - Atracurium has no known effect on consciousness, pain threshold, or cerebration. It should be used only with adequate anesthesia. - Atracurium besylate injection, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle. Depending on the resultant pH of such mixtures, atracurium may be inactivated and a free acid may be precipitated. - Atracurium besylate injection 10 mL multiple dose vials contain benzyl alcohol. In neonates, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal. Atracurium besylate 5 mL single use vials do not contain benzyl alcohol (see Precautions: Pediatric Use). - Severe anaphylactic reactions to neuromuscular blocking agents, including atracurium besylate, have been reported. These reactions have in some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported in this class of drugs. - Table 1 includes all adverse reaction reported attributable to atracurium during clinical trials with 875 patients. - Most adverse reactions were of little clinical significance unless they were associated with significant hemodynamic changes. Table 2 summarizes the incidences of substantial vital sign changes noted during atracurium clinical trials with 530 patients, without cardiovascular disease, in whom these parameters were assessed. [File:ATRACURIUMadverse2.jpg\|thumb\|none\|400px\|left\|This image is provided by the National Library of Medicine.]] - Based on initial clinical practice experience in approximately 3 million patients who received atracurium in the U.S. and in the United Kingdom, spontaneously reported adverse reactions were uncommon (approximately 0.01% to 0.02%). The following adverse reactions are among the most frequently reported, but there are insufficient data to support an estimate of their incidence: - Allergic reactions (anaphylactic or anaphylactoid responses) which, in rare instances, were severe (e.g., cardiac arrest) - Inadequate block, prolonged block - Hypotension, vasodilatation (flushing), tachycardia, bradycardia - Dyspnea, bronchospasm, laryngospasm - Rash, urticaria, reaction at injection site - There have been rare spontaneous reports of seizures in ICU patients following long-term infusion of atracurium to support mechanical ventilation. There are insufficient data to define the contribution, if any, of atracurium and/or its metabolite laudanosine. (See PRECAUTIONS: Long-Term Use in Intensive Care Unit [ICU]). - There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including atracurium besylate. These reactions, in some cases, have been life-threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see Warnings and Precautions). - If other muscle relaxants are used during the same procedure, the possibility of a synergistic or antagonist effect should be considered. - The prior administration of succinylcholine does not enhance the duration, but quickens the onset and may increase the depth, of neuromuscular block induced by atracurium besylate. Atracurium should not be administered until a patient has recovered from succinylcholine-induced neuromuscular block. - Atracurium besylate was administered subcutaneously on days 6 through 18 of gestation to nonventilated Dutch rabbits. Treatment groups were given either 0.15 mg/kg once daily or 0.10 mg/kg twice daily. Lethal respiratory distress occurred in two 0.15 mg/kg animals and in one 0.10 mg/kg animal, with transient respiratory distress or other evidence of neuromuscular block occurring in 10 of 19 and in 4 of 20 of the 0.15 mg/kg and 0.10 mg/kg animals, respectively. There was an increased incidence of certain spontaneously occurring visceral and skeletal anomalies or variations in one or both treated groups when compared to non-treated controls. The percentage of male fetuses was lower (41% vs. 51%) and the post-implantation losses were increased (15% vs. 8%) in the group given 0.15 mg/kg once daily when compared to the controls; the mean numbers of implants (6.5 vs. 4.4) and normal live fetuses (5.4 vs. 3.8) were greater in this group when compared to the control group. - Atracurium besylate (0.3 mg/kg) has been administered to 26 pregnant women during delivery by cesarean section. No harmful effects were attributable to atracurium in any of the neonates, although small amounts of atracurium were shown to cross the placental barrier. The possibility of respiratory depression in the neonate should always be considered following cesarean section during which a neuromuscular blocking agent has been administered. In patients receiving magnesium sulfate, the reversal of neuromuscular block may be unsatisfactory and the dose of atracurium besylate should be lowered as indicated. - Atracurium besylate should be administered intravenously. Do not give atracurium besylate by intramuscular administration. Intramuscular administration of atracurium besylate may result in tissue irritation and there are no clinical data to support this route of administration. - As with other neuromuscular blocking agents, the use of a peripheral nerve stimulator will permit the most advantageous use of atracurium besylate, minimizing the possibility of overdosage or underdosage, and assist in the evaluation of recovery. - An atracurium besylate dose of 0.4 to 0.5 mg/kg (1.7 to 2.2 times the ED95), given as an intravenous bolus injection, is the recommended initial dose for most patients. With this dose, good or excellent conditions for nonemergency intubation can be expected in 2 to 2.5 minutes in most patients, with maximum neuromuscular block achieved approximately 3 to 5 minutes after injection. Clinically required neuromuscular block generally lasts 20 to 35 minutes under balanced anesthesia. Under balanced anesthesia, recovery to 25% of control is achieved approximately 35 to 45 minutes after injection, and recovery is usually 95% complete approximately 60 minutes after injection. - Atracurium is potentiated by isoflurane or enflurane anesthesia. The same initial atracurium besylate dose of 0.4 to 0.5 mg/kg may be used for intubation prior to administration of these inhalation agents; however, if atracurium is first administered under steady-state of isoflurane or enflurane, the initial atracurium besylate dose should be reduced by approximately one-third, i.e., to 0.25 to 0.35 mg/kg, to adjust for the potentiating effects of these anesthetic agents. With halothane, which has only a marginal (approximately 20%) potentiating effect on atracurium, smaller dosage reductions may be considered. - Atracurium besylate doses of 0.08 to 0.10 mg/kg are recommended for maintenance of neuromuscular block during prolonged surgical procedures. * The first maintenance dose will generally be required 20 to 45 minutes after the initial atracurium besylate injection, but the need for maintenance doses should be determined by clinical criteria. Because atracurium lacks cumulative effects, maintenance doses may be administered at relatively regular intervals for each patient, ranging approximately from 15 to 25 minutes under balanced anesthesia, slightly longer under isoflurane or enflurane. Higher atracurium doses (up to 0.2 mg/kg) permit maintenance dosing at longer intervals. - No atracurium dosage adjustments are required for pediatric patients two years of age or older. An atracurium besylate dose of 0.3 to 0.4 mg/kg is recommended as the initial dose for infants (1 month to 2 years of age) under halothane anesthesia. Maintenance doses may be required with slightly greater frequency in infants and children than in adults. - An initial atracurium besylate dose of 0.3 to 0.4 mg/kg, given slowly or in divided doses over one minute, is recommended for adults, children, or infants with significant cardiovascular disease and for adults, children, or infants with any history (e.g., severe anaphylactoid reactions or asthma) suggesting a greater risk of histamine release. - Dosage reductions must be considered also in patients with neuromuscular disease, severe electrolyte disorders, or carcinomatosis in which potentiation of neuromuscular block or difficulties with reversal have been demonstrated. There has been no clinical experience with atracurium in these patients, and no specific dosage adjustments can be recommended. No atracurium dosage adjustments are required for patients with renal disease. - An initial atracurium besylate dose of 0.3 to 0.4 mg/kg is recommended for adults following the use of succinylcholine for intubation under balanced anesthesia. Further reductions may be desirable with the use of potent inhalation anesthetics. The patient should be permitted to recover from the effects of succinylcholine prior to atracurium administration. Insufficient data are available for recommendation of a specific initial atracurium dose for administration following the use of succinylcholine in children and infants. - After administration of a recommended initial bolus dose of atracurium besylate injection (0.3 to 0.5 mg/kg), a diluted solution of atracurium besylate can be administered by continuous infusion to adults and pediatric patients aged 2 or more years for maintenance of neuromuscular block during extended surgical procedures. - Infusion of atracurium should be individualized for each patient. The rate of administration should be adjusted according to the patient’s response as determined by peripheral nerve stimulation. Accurate dosing is best achieved using a precision infusion device. - Infusion of atracurium should be initiated only after early evidence of spontaneous recovery from the bolus dose. An initial infusion rate of 9 to 10 mcg/kg/min may be required to rapidly counteract the spontaneous recovery of neuromuscular function. Thereafter, a rate of 5 to 9 mcg/kg/min should be adequate to maintain continuous neuromuscular block in the range of 89% to 99% in most pediatric and adult patients under balanced anesthesia. Occasional patients may require infusion rates as low as 2 mcg/kg/min or as high as 15 mcg/kg/min. - The neuromuscular blocking effect of atracurium administered by infusion is potentiated by enflurane or isoflurane and, to a lesser extent, by halothane. Reduction in the infusion rate of atracurium should, therefore, be considered for patients receiving inhalation anesthesia. The rate of atracurium infusion should be reduced by approximately one-third in the presence of steady-state enflurane or isoflurane anesthesia; smaller reductions should be considered in the presence of halothane. - In patients undergoing cardiopulmonary bypass with induced hypothermia, the rate of infusion of atracurium required to maintain adequate surgical relaxation during hypothermia (25° to 28°C) has been shown to be approximately half the rate required during normothermia. - Spontaneous recovery from neuromuscular block following discontinuation of atracurium infusion may be expected to proceed at a rate comparable to that following administration of a single bolus dose. - The principles for infusion of atracurium in the OR are also applicable to use in the ICU. - An infusion rate of 11 to 13 mcg/kg/min (range: 4.5 to 29.5) should provide adequate neuromuscular block in adult patients in an ICU. Limited information suggests that infusion rates required for pediatric patients in the ICU may be higher than in adult patients. There may be wide interpatient variability in dosage requirements and these requirements may increase or decrease with time (see PRECAUTIONS: Long-Term Use in Intensive Care Unit [ICU]). Following recovery from neuromuscular block, readministration of a bolus dose may be necessary to quickly reestablish neuromuscular block prior to reinstitution of the infusion. - The amount of infusion solution required per minute will depend upon the concentration of atracurium in the infusion solution, the desired dose of atracurium, and the patient’s weight. The following tables provide guidelines for delivery, in mL/hr (equivalent to microdrops/min when 60 microdrops = 1 mL), of atracurium solutions in concentrations of 0.2 mg/mL (20 mg in 100 mL) or 0.5 mg/mL (50 mg in 100 mL) with an infusion pump or a gravity flow device. - Atracurium besylate infusion solutions may be prepared by admixing atracurium besylate injection with an appropriate diluent such as 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection. Infusion solutions should be used within 24 hours of preparation. Unused solutions should be discarded. Solutions containing 0.2 mg/mL or 0.5 mg/mL atracurium besylate in the above diluents may be stored either under refrigeration or at room temperature for 24 hours without significant loss of potency. Care should be taken during admixture to prevent inadvertent contamination. Visually inspect prior to administration. - Spontaneous degradation of atracurium besylate has been demonstrated to occur more rapidly in Lactated Ringer’s solution than in 0.9% sodium chloride solution. Therefore, it is recommended that Lactated Ringer’s Injection not be used as a diluent in preparing solutions of atracurium besylate injection for infusion. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - Three pediatric patients (3 weeks, 4 and 5 months of age) unintentionally received doses of 0.8 mg/kg to 1 mg/kg of atracurium besylate. The time to 25% recovery (50 to 55 minutes) following these doses, which were 5 to 6 times the ED95 dose, was moderately longer than the corresponding time observed following doses 2 to 2.5 times the atracurium ED95 dose in infants (22 to 36 minutes). Cardiovascular changes were minimal. Nonetheless the possibility of cardiovascular changes must be considered in the case of overdose. - An adult patient (17 years of age) unintentionally received an initial dose of 1.3 mg/kg of atracurium besylate. The time from injection to 25% recovery (83 minutes) was approximately twice that observed following maximum recommended doses in adults (35 to 45 minutes). The patient experienced moderate hemodynamic changes (13% increase in mean arterial pressure and 27% increase in heart rate) which persisted for 40 minutes and did not require treatment. - The intravenous LD50s determined in non-ventilated male and female albino mice and male Wistar rats were 1.9, 2.01 and 1.31 mg/kg, respectively. Deaths occurred within 2 minutes and were caused by respiratory paralysis. The subcutaneous LD50 determined in non-ventilated male Wistar rats was 282.8 mg/kg. Tremors, ptosis, loss of reflexes and respiratory failure preceded death which occurred 45 to 120 minutes after injection. - Atracurium besylate is a complex molecule containing four sites at which different stereochemical configurations can occur. The symmetry of the molecule, however, results in only ten, instead of sixteen, possible different isomers. The manufacture of atracurium besylate results in these isomers being produced in unequal amounts but with a consistent ratio. Those molecules in which the methyl group attached to the quaternary nitrogen projects on the opposite side to the adjacent substituted-benzyl moiety predominate by approximately 3:1. - Atracurium Besylate Injection USP is a sterile, non-pyrogenic aqueous solution. Each mL contains 10 mg atracurium besylate. The pH is adjusted to 3.00 to 3.65 with benzenesulfonic acid. The multiple dose vial contains 0.9% benzyl alcohol added as a preservative. Atracurium besylate injection slowly loses potency with time at the rate of approximately 6% per year under refrigeration (5°C). Atracurium besylate injection should be refrigerated at 2°C to 8°C (36°F to 46°F) to preserve potency. Rate of loss in potency increases to approximately 5% per month at 25°C (77°F). Upon removal from refrigeration to room temperature storage conditions (25°C / 77°F), use atracurium besylate injection within 14 days even if rerefrigerated. - The duration of neuromuscular block produced by atracurium is approximately one-third to one-half the duration of block by d-tubocurarine, metocurine, and pancuronium at initially equipotent doses. As with other nondepolarizing neuromuscular blockers, the time to onset of paralysis decreases and the duration of maximum effect increases with increasing atracurium doses. - The ED95 (dose required to produce 95% suppression of the muscle twitch response with balanced anesthesia) has averaged 0.23 mg/kg (0.11 to 0.26 mg/kg in various studies). An initial atracurium dose of 0.4 to 0.5 mg/kg generally produces maximum neuromuscular block within 3 to 5 minutes of injection, with good or excellent intubation conditions within 2 to 2.5 minutes in most patients. Recovery from neuromuscular block (under balanced anesthesia) can be expected to begin approximately 20 to 35 minutes after injection. Under balanced anesthesia, recovery to 25% of control is achieved approximately 35 to 45 minutes after injection, and recovery is usually 95% complete approximately 60 to 70 minutes after injection. The neuromuscular blocking action of atracurium is enhanced in the presence of potent inhalation anesthetics. Isoflurane and enflurane increase the potency of atracurium and prolong neuromuscular block by approximately 35%; however, halothane’s potentiating effect (approximately 20%) is marginal (see Dosage and administration). - Repeated administration of maintenance doses of atracurium has no cumulative effect on the duration of neuromuscular block if recovery is allowed to begin prior to repeat dosing. Moreover, the time needed to recover from repeat doses does not change with additional doses. Repeat doses can therefore be administered at relatively regular intervals with predictable results. After an initial dose of 0.4 to 0.5 mg/kg under balanced anesthesia, the first maintenance dose (suggested maintenance dose is 0.08 to 0.10 mg/kg) is generally required within 20 to 45 minutes, and subsequent maintenance doses are usually required at approximately 15 to 25 minute intervals. - Once recovery from atracurium’s neuromuscular blocking effects begins, it proceeds more rapidly than recovery from d-tubocurarine, metocurine, and pancuronium. Regardless of the atracurium dose, the time from start of recovery (from complete block) to complete (95%) recovery is approximately 30 minutes under balanced anesthesia, and approximately 40 minutes under halothane, enflurane or isoflurane. Repeated doses have no cumulative effect on recovery rate. - Reversal of neuromuscular block produced by atracurium can be achieved with an anti-cholinesterase agent such as neostigmine, edrophonium, or pyridostigmine, in conjunction with an anticholinergic agent such as atropine or glycopyrrolate. Under balanced anesthesia, reversal can usually be attempted approximately 20 to 35 minutes after an initial atracurium besylate dose of 0.4 to 0.5 mg/kg, or approximately 10 to 30 minutes after a 0.08 to 0.10 mg/kg maintenance dose, when recovery of muscle twitch has started. Complete reversal is usually attained within 8 to 10 minutes of the administration of reversing agents. Rare instances of breathing difficulties, possibly related to incomplete reversal, have been reported following attempted pharmacologic antagonism of atracurium-induced neuromuscular block. As with other agents in this class, the tendency for residual neuromuscular block is increased if reversal is attempted at deep levels of block or if inadequate doses of reversal agents are employed. - The pharmacokinetics of atracurium in humans are essentially linear within the 0.3 to 0.6 mg/kg dose range. The elimination half-life is approximately 20 minutes. The duration of neuromuscular block produced by atracurium besylate does not correlate with plasma pseudocholinesterase levels and is not altered by the absence of renal function. This is consistent with the results of in vitro studies which have shown that atracurium is inactivated in plasma via two nonoxidative pathways: ester hydrolysis, catalyzed by nonspecific esterases; and Hofmann elimination, a nonenzymatic chemical process which occurs at physiological pH. Some placental transfer occurs in humans. - Radiolabel studies demonstrated that atracurium undergoes extensive degradation in cats, and that neither kidney nor liver plays a major role in this elimination. Biliary and urinary excretion were the major routes of excretion of radioactivity (totaling >90% of the labeled dose within 7 hours of dosing), of which atracurium represented only a minor fraction. The metabolites in bile and urine were similar, including products of Hofmann elimination and ester hydrolysis. - Elderly patients may have slightly altered pharmacokinetic parameters compared to younger patients, with a slightly decreased total plasma clearance which is offset by a corresponding increase in volume of distribution. The net effect is that there has been no significant difference in clinical duration and recovery from neuromuscular block observed between elderly and younger patients receiving atracurium besylate. - Atracurium is a less potent histamine releaser than d-tubocurarine or metocurine. Histamine release is minimal with initial atracurium besylate doses up to 0.5 mg/kg, and hemodynamic changes are minimal within the recommended dose range. A moderate histamine release and significant falls in blood pressure have been seen following 0.6 mg/kg of atracurium besylate. The histamine and hemodynamic responses were poorly correlated. The effects were generally short-lived and manageable, but the possibility of substantial histamine release in sensitive individuals or in patients in whom substantial histamine release would be especially hazardous (e.g., patients with significant cardiovascular disease) must be considered. - It is not known whether the prior use of other nondepolarizing neuromuscular blocking agents has any effect on the activity of atracurium. The prior use of succinylcholine decreases by approximately 2 to 3 minutes the time to maximum block induced by atracurium besylate, and may increase the depth of block. Atracurium should be administered only after a patient recovers from succinylcholine-induced neuromuscular block.	https://www.wikidoc.org/index.php/Atracurium
9d069c539262ae305fa8bbd0697b6b82a674139c	wikidoc	Clofibrate	Clofibrate # Overview Clofibrate (tradename Atromid-S) is an organic compound. It is marketed as a fibrate. It is a lipid-lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood. It increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, and hence reduce the level of VLDL. It can increase the level of HDL as well. # Complications and controversies It can induce SIADH, syndrome of inappropriate secretion of antidiuretic hormone ADH (vasopressin). The World Health Organization Cooperative Trial on Primary Prevention of Ischaemic Heart Disease using clofibrate to lower serum cholesterol observed excess mortality in the clofibrate-treated group despite successful cholesterol lowering (47% more deaths during treatment with clofibrate and 5% after treatment with clofibrate) than the non-treated high cholesterol group. These deaths were due to a wide variety of causes other than heart disease, and remain "unexplained". Clofibrate was discontinued in 2002 due to adverse affects. # Synthesis	Clofibrate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Clofibrate (tradename Atromid-S) is an organic compound. It is marketed as a fibrate. It is a lipid-lowering agent used for controlling the high cholesterol and triacylglyceride level in the blood. It increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, and hence reduce the level of VLDL. It can increase the level of HDL as well. # Complications and controversies It can induce SIADH, syndrome of inappropriate secretion of antidiuretic hormone ADH (vasopressin). The World Health Organization Cooperative Trial on Primary Prevention of Ischaemic Heart Disease using clofibrate to lower serum cholesterol observed excess mortality in the clofibrate-treated group despite successful cholesterol lowering (47% more deaths during treatment with clofibrate and 5% after treatment with clofibrate) than the non-treated high cholesterol group. These deaths were due to a wide variety of causes other than heart disease, and remain "unexplained".[1] Clofibrate was discontinued in 2002 due to adverse affects. # Synthesis	https://www.wikidoc.org/index.php/Atromid-S
25b6dc862db35c1f0412acb54713ce77e9d7b8fb	wikidoc	Atrophin 1	Atrophin 1 Atrophin-1 is a protein that in humans is encoded by the ATN1 gene. The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat. The function of Atrophin-1 has not yet been determined. There is evidence provided by studies of Atrophin-1 in animals to suggest it acts as a transcriptional co-repressor. Atrophin-1 can be found in the nuclear and cytoplasmic compartments of neurons. It is expressed in nervous tissue. # Function The function of Atrophin-1 has not been defined yet. It is widely hypothesized that Atrophin-1 functions as a transcriptional co-repressor. A transcriptional co-repressor is a protein that indirectly suppresses the activity of specific genes by interacting with DNA-binding proteins. # Clinical significance The ATN1 gene has a segment of DNA called the CAG trinucleotide repeat. It is made up of cytosine, adenine, and guanine. The number of CAG repeats in the ATN1 gene in a healthy person will range from six to thirty-five repeats. CAG repeats that exceed thirty-five can cause a gain-of-function mutation in ATN1. Studies have supported the idea that mutated Atrophin-1 gathers in neurons and disrupts cell function. The sequence of the ATN1 gene contains a nuclear localizing signal (NLS) and a nuclear export signal (NES). It has been shown that a mutation of the NES in ATN1 can change where ATN1 localizes, and can cause aggregation to occur in the nucleus. This can lead to an increase in cellular toxicity. Mutations in ATN1 are associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy". Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia. The disorder is related to the expansion of a trinucleotide repeat within this gene. In patients with DRPLA, truncated ATN1 has been observed forming intranuclear aggregates that cause cell death. The symptoms of this disorder can be credited to the significant reduction of brain and spinal tissue observed in those afflicted with DRPLA. There are both juvenile-onset and late adult-onset variants of DRPLA, which show differing degrees of severity of specific symptoms. # Interactions ATN1 has been shown to interact with: - BAIAP2, - MAGI1, - MAGI2, - RERE, and - WWP2.	Atrophin 1 Atrophin-1 is a protein that in humans is encoded by the ATN1 gene.[1] The encoded protein includes a serine repeat and a region of alternating acidic and basic amino acids, as well as the variable glutamine repeat.[2] The function of Atrophin-1 has not yet been determined.[3] There is evidence provided by studies of Atrophin-1 in animals to suggest it acts as a transcriptional co-repressor.[3] Atrophin-1 can be found in the nuclear and cytoplasmic compartments of neurons.[3] It is expressed in nervous tissue.[4] # Function The function of Atrophin-1 has not been defined yet. It is widely hypothesized that Atrophin-1 functions as a transcriptional co-repressor.[5] A transcriptional co-repressor is a protein that indirectly suppresses the activity of specific genes by interacting with DNA-binding proteins.[5] # Clinical significance The ATN1 gene has a segment of DNA called the CAG trinucleotide repeat.[5] It is made up of cytosine, adenine, and guanine.[5] The number of CAG repeats in the ATN1 gene in a healthy person will range from six to thirty-five repeats.[5] CAG repeats that exceed thirty-five can cause a gain-of-function mutation in ATN1.[6] Studies have supported the idea that mutated Atrophin-1 gathers in neurons and disrupts cell function.[7] The sequence of the ATN1 gene contains a nuclear localizing signal (NLS) and a nuclear export signal (NES).[7] It has been shown that a mutation of the NES in ATN1 can change where ATN1 localizes, and can cause aggregation to occur in the nucleus.[7] This can lead to an increase in cellular toxicity.[7] Mutations in ATN1 are associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy". Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterized by cerebellar ataxia, myoclonic epilepsy, choreoathetosis, and dementia.[1] The disorder is related to the expansion of a trinucleotide repeat within this gene.[1] In patients with DRPLA, truncated ATN1 has been observed forming intranuclear aggregates that cause cell death.[7] The symptoms of this disorder can be credited to the significant reduction of brain and spinal tissue observed in those afflicted with DRPLA.[8] There are both juvenile-onset and late adult-onset variants of DRPLA, which show differing degrees of severity of specific symptoms.[8] # Interactions ATN1 has been shown to interact with: - BAIAP2,[9] - MAGI1,[10] - MAGI2,[10] - RERE,[11] and - WWP2.[10]	https://www.wikidoc.org/index.php/Atrophin_1
c1ff6bd8813db81ba881b32185d73cbb57c59d6e	wikidoc	Brain stem	Brain stem The brain stem is the lower part of the brain, adjoining and structurally continuous with the spinal cord. Most sources consider the pons, medulla oblongata, and midbrain all to be part of the brainstem. Differentiation of the brain stem from the cerebrum is complex, with regard to both anatomy and taxonomy. Some taxonomies describe the brain stem as the medulla and mesencephalon, whereas others include diencephalic regions. # General anatomy ## Ventral view/medulla and pons The most medial part of the medulla is the anterior median fissure. Moving laterally on each side are the pyramids. The pyramids contain the fibers of the corticospinal tract, or the upper motor neuronal axons as they head inferiorly to synapse on lower motor neuronal cell bodies within the ventral horn of the spinal cord. The anterolateral sulcus is lateral to the pyramids. Emerging from the anterolateral sulci are the hypoglossal nerve (CN XII) rootlets. Lateral to these rootlets and the anterolateral sulci are the olives. The olives are swellings in the medulla containing underlying inferior olivary nuclei (containing various nuclei and afferent fibers). Lateral (and dorsal) to the olives are the rootlets for cranial nerves IX and X (glossopharyngeal and vagus, respectively). The pyramids end at the pontomedullary junction, noted most obviously by the large basal pons. Between the basal pons, cranial nerve 6, 7 and 8 emerge (medial to lateral). These cranial nerves are the abducens nerve, facial nerve and the vestibulocochlear nerve, respectively. At the level of the midpons, the large trigeminal nerve, CN V, emerges. At the rostral pons, the occulomotor nerve emerges at the midline. Laterally, the trochlear nerve has emerged after emerging out of the dorsal rostral pons and wrapping around to the anterior. ## Dorsal view/medulla and pons The most medial part of the medulla is the posterior median fissure. Moving laterally on each side is the fasciculus gracilis, and lateral to that is the fasciculus cuneatus. Superior to each of these, and directly inferior to the obex, are the gracile tubercles and cuteanus tubercles, respectively. Underlying these are their respective nuclei. The obex marks the end of the 4th ventricle and the beginning of the central canal. The posterior intermediate sulci separates the fasciculi gracilis from the fasciculi cuneatus. Lateral to the fasciculi cuneatus is the lateral funiculus. Superior to the obex is the floor of the 4th ventricle. In the floor of the 4th ventricle, various nuclei can be visualized by the small bumps that they make in the overlying tissue. In the midline and directly superior to the obex is the vagal trigone and superior to that it the hypoglossal trigone. Underlying each of these are motor nuclei for the respective cranial nerves. Superior to these trigones are fibers running laterally in both directions. These fibers are known collectively as the striae medullares. Continuing in a rostral direction, the large bumps are called the facial colliculi. Each facial colliculus, contrary to their names, do not contain the facial nerve nuclei. Instead, they have facial nerve axons traversing superficial to underlying abducens (CN VI) nuclei. Lateral to all these bumps previously discussed is an indented line, or sulcus that runs rostrally, and is known as the sulcus limitans. This separates the medial motor neurons from the lateral sensory neurons. Lateral to the sulcus limitans is the area collectively known as the vestibular area, which is involved in special sensation. Moving rostrally, the inferior, middle, and superior cerebellar peduncles are found connecting the midbrain to the cerebellum. Directly rostral to the superior cerebellar peduncle, there is the superior medullary velum and then the two trochlear nerves. This marks the end of the pons as the inferior colliculus is directly rostral and marks the caudal midbrain. Spinal Cord to Medulla Transitional Landmark: From a ventral view, there can be seen a decussation of fibers between the two pyramids. This decussation marks the transition from medulla to spinal cord. Superior to the decussation is the medulla and inferior to it is the spinal cord. ## Midbrain The midbrain is divided into three parts. The first is the tectum, which is "roof" in Latin. The tectum includes the superior and inferior colliculi and is the dorsal covering of the cerebral aqueduct. The inferior colliculus, involved in the special sense of hearing sends its inferior brachium to the medial geniculate body of the diencephalon. Superior to the inferior colliculus, the superior colliculus marks the rostral midbrain. It is involved in the special sense of vision and sends its superior brachium to the lateral geniculate body of the diencephalon. The second part is the tegmentum and is ventral to the cerebral aqueduct. Several nuclei, tracts and the reticular formation is contained here. Last, the ventral side is comprised of paired cerebral peduncles. These transmit axons of upper motor neurons. ## Midbrain internal structures Periaqueductal Gray: The area around the cerebral aqueduct, which contains various neurons involved in the pain desensitization pathway. Neurons synapse here and, when stimulated, cause activation of neurons in the raphe nucleus magnus, which then project down into the dorsal horn of the spinal cord and prevent pain sensation transmission. Occulomotor nerve nucleus: This is the nucleus of CN III. Trochlear nerve nucleus: This is the nucleus of CN IV. Red Nucleus: This is a motor nucleus that sends a descending tract to the lower motor neurons. Substantia nigra: This is a concentration of neurons in the ventral portion of the midbrain that uses dopamine as its neurotransmitter and is involved in both motor function and emotion. Its dysfunction is implicated in Parkinson's Disease. Reticular formation: This is a large area in the midbrain that is involved in various important functions of the midbrain. In particular, it contains lowermotor neurons, is involved in the pain desensitization pathway, is involved in the arousal and consciousness systems, and contains the locus ceruleus, which is involved in intensive alertness modulation and in autonomic reflexes. Central tegmental tract: Directly anterior to the floor of the 4th ventricle, this is a pathway by which many tracts project up to the cortex and down to the spinal cord. # Embryology The adult human brainstem emerges from two of the three primary vesicles formed of the neural tube. The mesencephalon is the second of the three primary vesicles, and does not further differentiate into a secondary vesicle. This will become the midbrain. The third primary vesicle, the rhombencephalon, will further differentiate into two secondary vesicles, the metencephalon and the myelencephalon. The metencephalon will become the cerebellum and the pons. The myelencephalon will become the medulla. # Physiology There are three main functions of the brainstem. The first is its role in conduit functions. That is, all information related from the body to the cerebrum and cerebellum and vice versa, must traverse the brain stem. The ascending pathways coming from the body to the brain are the sensory pathways, and include the spinothalamic tract for pain and temperature sensation and the dorsal column, fasciculus gracilis, and cuneatus for touch, proprioception, and pressure sensation (both of the body). The facial sensations have similar pathways, and will travel in the spinothalamic tract and the medial lemniscus also). Descending tracts are upper motor neurons destined to synapse on lower motor neurons in the ventral horn and intermediate horn of the spinal cord. In addition, there are upper motor neurons that originate in the brainstem's vestibular, red, tactile, and reticular nuclei, which also descend and synapse in the spinal cord. Second, the cranial nerves 3-12 emerge from the brain stem. Third, the brain stem has integrative functions (it is involved in cardiovascular system control, respiratory control, pain sensitivity control, alertness, and consciousness). Thus, brain stem damage is a very serious and often life-threatening problem. The practical results of an improperly functioning brainstem are not just related to physical injury. Behavioral and physical signs can also manifest when there is incomplete pons or mid brain development. Such underdevelopment can affect behavior, academic performance, coordination, anxiety, speech, and focus. Habilitation, the process of first occurrence rehabilitation, makes use of programmatic exercise with the goals of completing development through inducement of neural plasticity # Physical signs of brainstem disease Diseases of the brainstem can result to abnormalities in the function of cranial nerves, which may lead to visual disturbances, pupil abnormalities, changes in sensation, muscle weakness, hearing problems, vertigo, swallowing and speech difficulty, voice change, and co-ordination problems. Less obvious cases may complain of poor reading comprehension, lack of focus, altered vigilance, clumsiness, or poor social skills. Often physical signs to an untrained examiner are not obvious as challenge testing (to reduce cortical compensations) are required during examination. Localizing neurological lesions in the brainstem may be very precise with imaging studies, although the clinical utility of such localization relies upon a clear understanding of brainstem anatomical structures on their functions. # Physical rehabilitation of brainstem disease While rehabilitation of brainstem disorders has traditionally belonged to the domain of physiatry or neurology more recently publicly accessible programs have become available that incorporate concepts which promote neural plasticity. At least one hospital system, Bon Sequours, St. Francis in Greenville, SC, has incorporated a movement based restorative therapy programs that focus on brainstem neuroplasticity for the treatment of common conditions such as Fibromyalgia.	Brain stem Template:Infobox Brain Editor-in-Chief: Robert G. Schwartz, M.D. [1], Piedmont Physical Medicine and Rehabilitation, P.A. The brain stem is the lower part of the brain, adjoining and structurally continuous with the spinal cord. Most sources consider the pons, medulla oblongata, and midbrain all to be part of the brainstem.[1] Differentiation of the brain stem from the cerebrum is complex, with regard to both anatomy and taxonomy. Some taxonomies describe the brain stem as the medulla and mesencephalon, whereas others include diencephalic regions. # General anatomy ## Ventral view/medulla and pons The most medial part of the medulla is the anterior median fissure. Moving laterally on each side are the pyramids. The pyramids contain the fibers of the corticospinal tract, or the upper motor neuronal axons as they head inferiorly to synapse on lower motor neuronal cell bodies within the ventral horn of the spinal cord. The anterolateral sulcus is lateral to the pyramids. Emerging from the anterolateral sulci are the hypoglossal nerve (CN XII) rootlets. Lateral to these rootlets and the anterolateral sulci are the olives. The olives are swellings in the medulla containing underlying inferior olivary nuclei (containing various nuclei and afferent fibers). Lateral (and dorsal) to the olives are the rootlets for cranial nerves IX and X (glossopharyngeal and vagus, respectively). The pyramids end at the pontomedullary junction, noted most obviously by the large basal pons. Between the basal pons, cranial nerve 6, 7 and 8 emerge (medial to lateral). These cranial nerves are the abducens nerve, facial nerve and the vestibulocochlear nerve, respectively. At the level of the midpons, the large trigeminal nerve, CN V, emerges. At the rostral pons, the occulomotor nerve emerges at the midline. Laterally, the trochlear nerve has emerged after emerging out of the dorsal rostral pons and wrapping around to the anterior. ## Dorsal view/medulla and pons The most medial part of the medulla is the posterior median fissure. Moving laterally on each side is the fasciculus gracilis, and lateral to that is the fasciculus cuneatus. Superior to each of these, and directly inferior to the obex, are the gracile tubercles and cuteanus tubercles, respectively. Underlying these are their respective nuclei. The obex marks the end of the 4th ventricle and the beginning of the central canal. The posterior intermediate sulci separates the fasciculi gracilis from the fasciculi cuneatus. Lateral to the fasciculi cuneatus is the lateral funiculus. Superior to the obex is the floor of the 4th ventricle. In the floor of the 4th ventricle, various nuclei can be visualized by the small bumps that they make in the overlying tissue. In the midline and directly superior to the obex is the vagal trigone and superior to that it the hypoglossal trigone. Underlying each of these are motor nuclei for the respective cranial nerves. Superior to these trigones are fibers running laterally in both directions. These fibers are known collectively as the striae medullares. Continuing in a rostral direction, the large bumps are called the facial colliculi. Each facial colliculus, contrary to their names, do not contain the facial nerve nuclei. Instead, they have facial nerve axons traversing superficial to underlying abducens (CN VI) nuclei. Lateral to all these bumps previously discussed is an indented line, or sulcus that runs rostrally, and is known as the sulcus limitans. This separates the medial motor neurons from the lateral sensory neurons. Lateral to the sulcus limitans is the area collectively known as the vestibular area, which is involved in special sensation. Moving rostrally, the inferior, middle, and superior cerebellar peduncles are found connecting the midbrain to the cerebellum. Directly rostral to the superior cerebellar peduncle, there is the superior medullary velum and then the two trochlear nerves. This marks the end of the pons as the inferior colliculus is directly rostral and marks the caudal midbrain. Spinal Cord to Medulla Transitional Landmark: From a ventral view, there can be seen a decussation of fibers between the two pyramids. This decussation marks the transition from medulla to spinal cord. Superior to the decussation is the medulla and inferior to it is the spinal cord. ## Midbrain The midbrain is divided into three parts. The first is the tectum, which is "roof" in Latin. The tectum includes the superior and inferior colliculi and is the dorsal covering of the cerebral aqueduct. The inferior colliculus, involved in the special sense of hearing sends its inferior brachium to the medial geniculate body of the diencephalon. Superior to the inferior colliculus, the superior colliculus marks the rostral midbrain. It is involved in the special sense of vision and sends its superior brachium to the lateral geniculate body of the diencephalon. The second part is the tegmentum and is ventral to the cerebral aqueduct. Several nuclei, tracts and the reticular formation is contained here. Last, the ventral side is comprised of paired cerebral peduncles. These transmit axons of upper motor neurons. ## Midbrain internal structures Periaqueductal Gray: The area around the cerebral aqueduct, which contains various neurons involved in the pain desensitization pathway. Neurons synapse here and, when stimulated, cause activation of neurons in the raphe nucleus magnus, which then project down into the dorsal horn of the spinal cord and prevent pain sensation transmission. Occulomotor nerve nucleus: This is the nucleus of CN III. Trochlear nerve nucleus: This is the nucleus of CN IV. Red Nucleus: This is a motor nucleus that sends a descending tract to the lower motor neurons. Substantia nigra: This is a concentration of neurons in the ventral portion of the midbrain that uses dopamine as its neurotransmitter and is involved in both motor function and emotion. Its dysfunction is implicated in Parkinson's Disease. Reticular formation: This is a large area in the midbrain that is involved in various important functions of the midbrain. In particular, it contains lowermotor neurons, is involved in the pain desensitization pathway, is involved in the arousal and consciousness systems, and contains the locus ceruleus, which is involved in intensive alertness modulation and in autonomic reflexes. Central tegmental tract: Directly anterior to the floor of the 4th ventricle, this is a pathway by which many tracts project up to the cortex and down to the spinal cord. # Embryology The adult human brainstem emerges from two of the three primary vesicles formed of the neural tube. The mesencephalon is the second of the three primary vesicles, and does not further differentiate into a secondary vesicle. This will become the midbrain. The third primary vesicle, the rhombencephalon, will further differentiate into two secondary vesicles, the metencephalon and the myelencephalon. The metencephalon will become the cerebellum and the pons. The myelencephalon will become the medulla. # Physiology There are three main functions of the brainstem. The first is its role in conduit functions. That is, all information related from the body to the cerebrum and cerebellum and vice versa, must traverse the brain stem. The ascending pathways coming from the body to the brain are the sensory pathways, and include the spinothalamic tract for pain and temperature sensation and the dorsal column, fasciculus gracilis, and cuneatus for touch, proprioception, and pressure sensation (both of the body). The facial sensations have similar pathways, and will travel in the spinothalamic tract and the medial lemniscus also). Descending tracts are upper motor neurons destined to synapse on lower motor neurons in the ventral horn and intermediate horn of the spinal cord. In addition, there are upper motor neurons that originate in the brainstem's vestibular, red, tactile, and reticular nuclei, which also descend and synapse in the spinal cord. Second, the cranial nerves 3-12 emerge from the brain stem. Third, the brain stem has integrative functions (it is involved in cardiovascular system control, respiratory control, pain sensitivity control, alertness, and consciousness). Thus, brain stem damage is a very serious and often life-threatening problem. The practical results of an improperly functioning brainstem are not just related to physical injury. Behavioral and physical signs can also manifest when there is incomplete pons or mid brain development. Such underdevelopment can affect behavior, academic performance, coordination, anxiety, speech, and focus. Habilitation, the process of first occurrence rehabilitation, makes use of programmatic exercise with the goals of completing development through inducement of neural plasticity # Physical signs of brainstem disease Diseases of the brainstem can result to abnormalities in the function of cranial nerves, which may lead to visual disturbances, pupil abnormalities, changes in sensation, muscle weakness, hearing problems, vertigo, swallowing and speech difficulty, voice change, and co-ordination problems. Less obvious cases may complain of poor reading comprehension, lack of focus, altered vigilance, clumsiness, or poor social skills. Often physical signs to an untrained examiner are not obvious as challenge testing (to reduce cortical compensations) are required during examination. Localizing neurological lesions in the brainstem may be very precise with imaging studies, although the clinical utility of such localization relies upon a clear understanding of brainstem anatomical structures on their functions. # Physical rehabilitation of brainstem disease While rehabilitation of brainstem disorders has traditionally belonged to the domain of physiatry or neurology more recently publicly accessible programs have become available that incorporate concepts which promote neural plasticity. [2] At least one hospital system, Bon Sequours, St. Francis in Greenville, SC, has incorporated a movement based restorative therapy programs that focus on brainstem neuroplasticity for the treatment of common conditions such as Fibromyalgia.	https://www.wikidoc.org/index.php/Auditory_brainstem
caa7c09404da94d27099bc034b3d4fb98ac990d0	wikidoc	Oblimersen	Oblimersen # Overview Oblimersen (INN, trade name Genasense; also known as Augmerosen and bcl-2 antisense oligodeoxynucleotide G3139) is an antisense oligodeoxyribonucleotide being studied as a possible treatment for several types of cancer, including chronic lymphocytic leukemia, B-cell lymphoma, and breast cancer. It may kill cancer cells by blocking the production of Bcl-2—a protein that makes cancer cells live longer—and by making them more sensitive to chemotherapy. # History An antisense oligonucleotide drug Genasense (G3139) has been developed by Genta Incorporated to target Bcl-2. An antisense DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). An antisense drug is a short sequence of RNA which hybridises with and inactivates mRNA, preventing the protein from being formed. It was shown that the proliferation of human lymphoma cells (with t(14;18) translocation) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. In vitro studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA. These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial was launched in 2004. By the first quarter 2010, Genasense had not received FDA approval due to disappointing results in a melanoma trial. Although safety and efficacy of Genasense have not been established for any use, Genta Incorporated still claims on its website that studies are currently underway to examine the potential role of Genasense in a variety of clinical indications.	Oblimersen Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Oblimersen (INN, trade name Genasense; also known as Augmerosen and bcl-2 antisense oligodeoxynucleotide G3139) is an antisense oligodeoxyribonucleotide being studied as a possible treatment for several types of cancer, including chronic lymphocytic leukemia, B-cell lymphoma, and breast cancer. It may kill cancer cells by blocking the production of Bcl-2—a protein that makes cancer cells live longer—and by making them more sensitive to chemotherapy. # History An antisense oligonucleotide drug Genasense (G3139) has been developed by Genta Incorporated to target Bcl-2. An antisense DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). An antisense drug is a short sequence of RNA which hybridises with and inactivates mRNA, preventing the protein from being formed. It was shown that the proliferation of human lymphoma cells (with t(14;18) translocation) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. In vitro studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA.[1] These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial was launched in 2004.[2] By the first quarter 2010, Genasense had not received FDA approval due to disappointing results in a melanoma trial. Although safety and efficacy of Genasense have not been established for any use, Genta Incorporated still claims on its website that studies are currently underway to examine the potential role of Genasense in a variety of clinical indications.	https://www.wikidoc.org/index.php/Augmerosen
ebbaae26a03be041d203a285765fb2cbe5de5e19	wikidoc	Auramine O	Auramine O Auramine O, also called Basic yellow 2, Pyocatanium aureum, aizen auramine, Pyoktanin Yellow, Canary Yellow, Pyoktanin, or C.I. 41000, is a diarylmethane dye used as a fluorescent stain. In its pure form, Auramine O appears as yellow needle crystals. It is very soluble in water and soluble in ethanol. Auramine O can be used to stain acid-fast bacteria (e.g. Mycobacterium), where it binds to the mycolic acid in its cell wall) in a way similar to Ziehl-Neelsen stain. It can also be used as a fluorescent version of Schiff reagent. Auramine O can be used together with Rhodamine B as the Truant auramine-rhodamine stain for Mycobacterium tuberculosis. It can be also used as an antiseptic agent. # Safety Its risk and safety phrases are Template:R22 Template:R24 Template:R40 Template:S36/37 Template:S45.	Auramine O Auramine O, also called Basic yellow 2, Pyocatanium aureum, aizen auramine, Pyoktanin Yellow, Canary Yellow, Pyoktanin, or C.I. 41000, is a diarylmethane dye used as a fluorescent stain. In its pure form, Auramine O appears as yellow needle crystals. It is very soluble in water and soluble in ethanol. Auramine O can be used to stain acid-fast bacteria (e.g. Mycobacterium), where it binds to the mycolic acid in its cell wall) in a way similar to Ziehl-Neelsen stain.[1] It can also be used as a fluorescent version of Schiff reagent.[2] Auramine O can be used together with Rhodamine B as the Truant auramine-rhodamine stain for Mycobacterium tuberculosis.[3][4] It can be also used as an antiseptic agent. Template:SMILESCAS # Safety Its risk and safety phrases are Template:R22 Template:R24 Template:R40 Template:S36/37 Template:S45.	https://www.wikidoc.org/index.php/Auramine_O
a28f6f1d47916fd3a02108e069a599753d9d8a49	wikidoc	Irbesartan	Irbesartan # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Irbesartan is an Angiotensin 2 Receptor Blocker that is FDA approved for the treatment of hypertension, Nephropathy in Type 2 Diabetic Patients. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, heartburn，headache，upper respiratory infection, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information - Recommended initial dosage: 150 mg PO qd. Patients requiring further reduction in blood pressure should be titrated to 300 mg PO qd or bid - A low dose of a diuretic may be added, if blood pressure is not controlled by irbesartan tablets USP alone. - Hydrochlorothiazide has been shown to have an additive effect. - No dosage adjustment is necessary in elderly patients, or in patients with hepatic impairment or mild to severe renal impairment. ### Nephropathy in Type 2 Diabetic Patients - Indication - Irbesartan tablets USP are indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (> 300 mg/day) in patients with type 2 diabetes and hypertension. In this population, irbesartan tablets USP reduce the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation). - Dosing information - Recommended target maintenance dosage: 300 mg PO qd. There are no data on the clinical effects of lower doses of irbesartan tablets USP on diabetic nephropathy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Heart Failure - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level A - Dosing Information - ARBs are recommended in patients who are intolerant of an ACE inhibitor. ### Non–Guideline-Supported Use ### Atrial fibrillation - Dosing information - 150 mg/day, which could be increased to 300 mg/day ### Left ventricular hypertrophy - Dosing information - 150 mg/day, # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Irbesartan FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Irbesartan in pediatric patients. ### Non–Guideline-Supported Use ### Chronic Renal impairment - Dosing information - For those weighing 10 to 20 kilograms (kg): 37.5 mg/day - For those weighing 21 to 40 kg:75 mg/day - For those weighing over 40 kg: 150 mg/day - For those weighing 35 kilograms (kg) or less: 75 mg/day - For those above 35 kg: 150 mg PO qd # Contraindications Irbesartan is contraindicated in patients who are hypersensitive to any component of this product. Do not coadminister aliskiren with Irbesartan in patients with diabetes. # Warnings ### Pregnancy Category D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Irbesartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Irbesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Irbesartan for hypotension, oliguria, and hyperkalemia. - When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, and 650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses ≥50 mg/kg/day (approximately equivalent to the maximum recommended human dose , 300 mg/day, on a body surface area basis). Subcutaneous edema was observed in fetuses at doses ≥180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits. - Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan. ### Hypotension in Volume- or Salt-Depleted Patients - Excessive reduction of blood pressure was rarely seen (<0.1%) in patients with uncomplicated hypertension. Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, eg, in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should be corrected prior to administration of Irbesartan, or a low starting dose should be used. - If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. ## PRECAUTIONS ### Impaired Renal Function - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure), treatment with angiotensin-converting-enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Irbesartan would be expected to behave similarly. - In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. There has been no known use of Irbesartan in patients with unilateral or bilateral renal artery stenosis, but a similar effect should be anticipated. ### Information for Patients - Female patients of childbearing age should be told about the consequences of exposure to Irbesartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. # Adverse Reactions ## Clinical Trials Experience ## Hypertension - Irbesartan has been evaluated for safety in more than 4300 patients with hypertension and about 5000 subjects overall. This experience includes 1303 patients treated for over 6 months and 407 patients for 1 year or more. Treatment with Irbesartan was well-tolerated, with an incidence of adverse events similar to placebo. These events generally were mild and transient with no relationship to the dose of Irbesartan. - In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event was required in 3.3% of patients treated with Irbesartan, versus 4.5% of patients given placebo. - In placebo-controlled clinical trials, the following adverse event experiences reported in at least 1% of patients treated with Irbesartan (n=1965) and at a higher incidence versus placebo (n=641), excluding those too general to be informative and those not reasonably associated with the use of drug because they were associated with the condition being treated or are very common in the treated population, include: diarrhea (3% vs 2%), dyspepsia/heartburn (2% vs 1%), and fatigue (4% vs 3%). - The following adverse events occurred at an incidence of 1% or greater in patients treated with irbesartan, but were at least as frequent or more frequent in patients receiving placebo: abdominal pain, anxiety/nervousness, chest pain, dizziness, edema, headache, influenza, musculoskeletal pain, pharyngitis, nausea/vomiting, rash, rhinitis, sinus abnormality, tachycardia, and urinary tract infection. - Irbesartan use was not associated with an increased incidence of dry cough, as is typically associated with ACE inhibitor use. In placebo-controlled studies, the incidence of cough in irbesartan-treated patients was 2.8% versus 2.7% in patients receiving placebo. - The incidence of hypotension or orthostatic hypotension was low in irbesartan- treated patients (0.4%), unrelated to dosage, and similar to the incidence among placebo-treated patients (0.2%). Dizziness, syncope, and vertigo were reported with equal or less frequency in patients receiving irbesartan compared with placebo. - In addition, the following potentially important events occurred in less than 1% of the 1965 patients and at least 5 patients (0.3%) receiving irbesartan in clinical studies, and those less frequent, clinically significant events (listed by body system). It cannot be determined whether these events were causally related to irbesartan: Body as a Whole: fever, chills, facial edema, upper extremity edema Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, arrhythmic/conduction disorder, cardio-respiratory arrest, heart failure, hypertensive crisis Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout Gastrointestinal: constipation, oral lesion, gastroenteritis, flatulence, abdominal distention Musculoskeletal/Connective Tissue: extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness Nervous System: sleep disturbance, numbness, somnolence, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident Renal/Genitourinary: abnormal urination, prostate disorder Respiratory: epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis, other eye disturbance, eyelid abnormality, ear abnormality ## Nephropathy in Type 2 Diabetic Patients - In clinical studies in patients with hypertension and type 2 diabetic renal disease, the adverse drug experiences were similar to those seen in patients with hypertension with the exception of an increased incidence of orthostatic symptoms (dizziness, orthostatic dizziness, and orthostatic hypotension) observed in IDNT (proteinuria ≥900 mg/day, and serum creatinine ranging from 1.0–3.0 mg/dL). In this trial, orthostatic symptoms occurred more frequently in the Irbesartan group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatic hypotension 5.4%) than in the placebo group (dizziness 6.0%, orthostatic dizziness 2.7%, orthostatic hypotension 3.2%). ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Irbesartan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Irbesartan. - The following have been reported: urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); increased liver function tests; jaundice; hepatitis; hyperkalemia, and thrombocytopenia. - Impaired renal function, including cases of renal failure, has been reported. - Cases of increased CPK and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. ## Laboratory Test Findings ### Hypertension - In controlled clinical trials, clinically important differences in laboratory tests were rarely associated with administration of Irbesartan. ### Creatinine, Blood Urea Nitrogen - Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.7% of patients with essential hypertension treated with Irbesartan alone versus 0.9% on placebo. ### Hematologic - Mean decreases in hemoglobin of 0.2 g/dL were observed in 0.2% of patients receiving Irbesartan compared to 0.3% of placebo-treated patients. Neutropenia (<1000 cells/mm3) occurred at similar frequencies among patients receiving Irbesartan (0.3%) and placebo-treated patients (0.5%). - Nephropathy in Type 2 Diabetic Patients ### Hyperkalemia - In IDNT (proteinuria ≥900 mg/day, and serum creatinine ranging from 1.0–3.0 mg/dL), the percent of patients with hyperkalemia (>6 mEq/L) was 18.6% in the Irbesartan group versus 6.0% in the placebo group. Discontinuations due to hyperkalemia in the Irbesartan group were 2.1% versus 0.4% in the placebo group. # Drug Interactions - No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine. - In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP 2C9 substrates/inhibitors sulphenazole, tolbutamide and nifedipine. However, in clinical studies the consequences of concomitant irbesartan on the pharmacodynamics of warfarin were negligible. Based on in vitrodata, no interaction would be expected with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4. - In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days had no effect on the pharmacodynamics of warfarin prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were not affected by coadministration of nifedipine or hydrochlorothiazide. - Concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. - Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including irbesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving irbesartan and NSAID therapy. - The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors. - Dual Blockade of the Renin-Angiotensin System (RAS) - Dual blockade of the RAS with angiotensin-receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on Irbesartan and other agents that affect the RAS. - Do not coadminister aliskiren with Irbesartan in patients with diabetes. Avoid use of aliskiren with Irbesartan in patients with renal impairment (GFR <60 mL/min). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Irbesartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Irbesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Irbesartan for hypotension, oliguria, and hyperkalemia. - When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, and 650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses ≥50 mg/kg/day (approximately equivalent to the maximum recommended human dose , 300 mg/day, on a body surface area basis). Subcutaneous edema was observed in fetuses at doses ≥180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits. - Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Irbesartan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Irbesartan during labor and delivery. ### Nursing Mothers - It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Neonates with a history of in utero exposure to irbesartan: - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. - Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to 16 years. - Irbesartan has not been studied in pediatric patients less than 6 years old. ### Geriatic Use - Of 4925 subjects receiving irbesartan in controlled clinical studies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3.0%) were 75 years and over. No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations, and Clinical Studies). ### Gender There is no FDA guidance on the use of Irbesartan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Irbesartan with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Irbesartan in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Irbesartan in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Irbesartan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Irbesartan in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring FDA Package Insert for Irbesartan contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - No data are available in regard to overdosage in humans. However, daily doses of 900 mg for 8 weeks were well-tolerated. The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. Irbesartan is not removed by hemodialysis. - To obtain up-to-date information about the treatment of overdosage, a good resource is a certified regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians' Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug interactions, drug-drug interactions, and unusual drug kinetics in the patient. - Laboratory determinations of serum levels of irbesartan are not widely available, and such determinations have, in any event, no known established role in the management of irbesartan overdose. - Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25- and 50-fold the MRHD (300 mg) on a mg/m2 basis, respectively. # Pharmacology ## Mechanism of Action - Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system (RAS) and also stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor. There is also an AT2 receptor in many tissues, but it is not involved in cardiovascular homeostasis. Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (more than 8500 fold) for the AT1 receptor than for the AT2 receptor and no agonist activity. - Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure. - Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Because irbesartan does not inhibit ACE, it does not affect the response to bradykinin; whether this has clinical relevance is not known. ## Structure - Irbesartan®- (irbesartan) is an angiotensin II receptor (AT1 subtype) antagonist. - Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3--1,3-diazaspironon-1-en-4-one. - Its empirical formula is C25H28N6O, and the structural formula: - Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water. ## Pharmacodynamics - In healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions. Inhibition was complete (100%) 4 hours following oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours (60% and 40% at 300 mg and 150 mg, respectively). - In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan causes a 1.5- to 2-fold rise in angiotensin II plasma concentration and a 2- to 3-fold increase in plasma renin levels. Aldosterone plasma concentrations generally decline following irbesartan administration, but serum potassium levels are not significantly affected at recommended doses. - In hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had no effect on glomerular filtration rate, renal plasma flow, or filtration fraction. In multiple dose studies in hypertensive patients, there were no clinically important effects on fasting triglycerides, total cholesterol, HDL-cholesterol, or fasting glucose concentrations. There was no effect on serum uric acid during chronic oral administration, and no uricosuric effect. ## Pharmacokinetics Irbesartan is an orally active agent that does not require biotransformation into an active form. The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% to 80%. Following oral administration of Irbesartan, peak plasma concentrations of irbesartan are attained at 1.5 to 2 hours after dosing. Food does not affect the bioavailability of Irbesartan. - Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range. - The terminal elimination half-life of irbesartan averaged 11 to 15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing. ## Metabolism and Elimination - Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of 14C-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to irbesartan's pharmacologic activity. - Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of 14C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide. - In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4. ## Distribution - Irbesartan is 90% bound to serum proteins (primarily albumin and α1-acid glycoprotein) with negligible binding to cellular components of blood. The average volume of distribution is 53 liters to 93 liters. Total plasma and renal clearances are in the range of 157 mL/min to 176 mL/min and 3.0 mL/min to 3.5 mL/min, respectively. With repetitive dosing, irbesartan accumulates to no clinically relevant extent. - Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta. Irbesartan is excreted in the milk of lactating rats. ## Special Populations ### Gender - No gender-related differences in pharmacokinetics were observed in healthy elderly (age 65–80 years) or in healthy young (age 18–40 years) subjects. In studies of hypertensive patients, there was no gender difference in half-life or accumulation, but somewhat higher plasma concentrations of irbesartan were observed in females (11–44%). No gender-related dosage adjustment is necessary. ### Geriatric - In elderly subjects (age 65–80 years), irbesartan elimination half-life was not significantly altered, but AUC and Cmax values were about 20% to 50% greater than those of young subjects (age 18–40 years). No dosage adjustment is necessary in the elderly. ### Race - In healthy black subjects, irbesartan AUC values were approximately 25% greater than whites; there were no differences in Cmax values. ### Renal Insufficiency - The pharmacokinetics of irbesartan were not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted. ### Hepatic Insufficiency - The pharmacokinetics of irbesartan following repeated oral administration were not significantly affected in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500/1000 mg/kg/day (males/females, respectively) in rats and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500 mg/kg/day provided an average systemic exposure to irbesartan (AUC0–24 hour, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure in humans receiving the maximum recommended dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to females only) provided an average systemic exposure about 21 times that reported for humans at the MRD. For male and female mice, 1000 mg/kg/day provided an exposure to irbesartan about 3 and 5 times, respectively, the human exposure at 300 mg/day. - Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro-human lymphocyte assay; in vivo-mouse micronucleus study). - Irbesartan had no adverse effects on fertility or mating of male or female rats at oral doses ≤650 mg/kg/day, the highest dose providing a systemic exposure to irbesartan (AUC0–24 hour, bound plus unbound) about 5 times that found in humans receiving the maximum recommended dose of 300 mg/day. # Clinical Studies ## Hypertension - The antihypertensive effects of Irbesartan (irbesartan) were examined in 7 major placebo-controlled 8 to 12 week trials in patients with baseline diastolic blood pressures of 95 mmHg to 110 mmHg. Doses of 1 mg to 900 mg were included in these trials in order to fully explore the dose-range of irbesartan. These studies allowed comparison of once- or twice-daily regimens at 150 mg/day, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Two of the 7 placebo-controlled trials identified above examined the antihypertensive effects of irbesartan and hydrochlorothiazide in combination. - The 7 studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan (1–900 mg) and 611 patients randomized to placebo. Once-daily doses of 150 mg and 300 mg provided statistically and clinically significant decreases in systolic and diastolic blood pressure with trough (24 hours post-dose) effects after 6 to 12 weeks of treatment compared to placebo, of about 8–10/5–6 mmHg and 8–12/5–8 mmHg, respectively. No further increase in effect was seen at dosages greater than 300 mg. The dose-response relationships for effects on systolic and diastolic pressure are shown in Figures 1 and 2. - Once-daily administration of therapeutic doses of irbesartan gave peak effects at around 3 to 6 hours and, in one ambulatory blood pressure monitoring study, again around 14 hours. This was seen with both once-daily and twice-daily dosing. Trough-to-peak ratios for systolic and diastolic response were generally between 60% to 70%. In a continuous ambulatory blood pressure monitoring study, once-daily dosing with 150 mg gave trough and mean 24-hour responses similar to those observed in patients receiving twice-daily dosing at the same total daily dose. - In controlled trials, the addition of irbesartan to hydrochlorothiazidedoses of 6.25 mg, 12.5 mg, or 25 mg produced further dose-related reductions in blood pressure similar to those achieved with the same monotherapy dose of irbesartan. HCTZ also had an approximately additive effect. - Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65 years of age, had generally similar responses. Irbesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population). - The effect of irbesartan is apparent after the first dose, and it is close to its full observed effect at 2 weeks. At the end of an 8-week exposure, about 2/3 of the antihypertensive effect was still present one week after the last dose. Rebound hypertension was not observed. There was essentially no change in average heart rate in irbesartan-treated patients in controlled trials. ## Nephropathy in Type 2 Diabetic Patients - The Irbesartan Diabetic Nephropathy Trial (IDNT) was a randomized, placebo- and active-controlled, double-blind, multicenter study conducted worldwide in 1715 patients with type 2 diabetes, hypertension (SeSBP >135 mmHg or SeDBP >85 mmHg), and nephropathy (serum creatinine 1.0 to 3.0 mg/dL in females or 1.2 to 3.0 mg/dL in males and proteinuria ≥900 mg/day). Patients were randomized to receive Irbesartan 75 mg, amlodipine 2.5 mg, or matching placebo once-daily. Patients were titrated to a maintenance dose of Irbesartan 300 mg, or amlodipine 10 mg, as tolerated. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and calcium channel blockers) were added as needed to achieve blood pressure goal (≤135/85 or 10 mmHg reduction in systolic blood pressure if higher than 160 mmHg) for patients in all groups. - The study population was 66.5% male, 72.9% below 65 years of age and 72% White, (Asian/Pacific Islander 5.0%, Black 13.3%, Hispanic 4.8%). The mean baseline seated systolic and diastolic blood pressures were 159 mmHg and 87 mmHg, respectively. The patients entered the trial with a mean serum creatinine of 1.7 mg/dL and mean proteinuria of 4144 mg/day. - The mean blood pressure achieved was 142/77 mmHg for Irbesartan, 142/76 mmHg for amlodipine, and 145/79 mmHg for placebo. Overall, 83.0% of patients received the target dose of irbesartan more than 50% of the time. Patients were followed for a mean duration of 2.6 years. - The primary composite endpoint was the time to occurrence of any one of the following events: doubling of baseline serum creatinine, end-stage renal disease (ESRD; defined by serum creatinine ≥6 mg/dL, dialysis, or renal transplantation) or death. Treatment with Irbesartan resulted in a 20% risk reduction versus placebo (p=0.0234) (see Figure 3 and Table 1). Treatment with Irbesartan also reduced the occurrence of sustained doubling of serum creatinine as a separate endpoint (33%), but had no significant effect on ESRD alone and no effect on overall mortality (see Table 1). - The percentages of patients experiencing an event during the course of the study can be seen in Table 1 below: - The secondary endpoint of the study was a composite of cardiovascular mortality and morbidity (myocardial infarction, hospitalization for heart failure, stroke with permanent neurological deficit, amputation). There were no statistically significant differences among treatment groups in these endpoints. Compared with placebo, Irbesartan significantly reduced proteinuria by about 27%, an effect that was evident within 3 months of starting therapy. Irbesartan significantly reduced the rate of loss of renal function (glomerular filtration rate), as measured by the reciprocal of the serum creatinine concentration, by 18.2%. - Table 2 presents results for demographic subgroups. Subgroup analyses are difficult to interpret and it is not known whether these observations represent true differences or chance effects. For the primary endpoint, Irbesartan's favorable effects were seen in patients also taking other antihypertensive medications (angiotensin II receptor antagonists, angiotensin-converting-enzyme inhibitors and calcium channel blockers were not allowed), oral hypoglycemic agents, and lipid-lowering agents. # How Supplied - Irbesartan tablets USP are available as follows: ## Storage - Store at 20° to 25°C (68° to 77°F) . - Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Pregnancy - Female patients of childbearing age should be told about the consequences of exposure to irbesartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. # Precautions with Alcohol Alcohol-Irbesartan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Avapro # Look-Alike Drug Names There is limited information about the Look-Alike Drug Names. # Drug Shortage Status # Price	Irbesartan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2], Rabin Bista, M.B.B.S. [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Irbesartan is an Angiotensin 2 Receptor Blocker that is FDA approved for the treatment of hypertension, Nephropathy in Type 2 Diabetic Patients. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, heartburn，headache，upper respiratory infection, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information - Recommended initial dosage: 150 mg PO qd. Patients requiring further reduction in blood pressure should be titrated to 300 mg PO qd or bid - A low dose of a diuretic may be added, if blood pressure is not controlled by irbesartan tablets USP alone. - Hydrochlorothiazide has been shown to have an additive effect. - No dosage adjustment is necessary in elderly patients, or in patients with hepatic impairment or mild to severe renal impairment. ### Nephropathy in Type 2 Diabetic Patients - Indication - Irbesartan tablets USP are indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (> 300 mg/day) in patients with type 2 diabetes and hypertension. In this population, irbesartan tablets USP reduce the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation). - Dosing information - Recommended target maintenance dosage: 300 mg PO qd. There are no data on the clinical effects of lower doses of irbesartan tablets USP on diabetic nephropathy. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use ### Heart Failure - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level A - Dosing Information - ARBs are recommended in patients who are intolerant of an ACE inhibitor. ### Non–Guideline-Supported Use ### Atrial fibrillation - Dosing information - 150 mg/day, which could be increased to 300 mg/day [1] ### Left ventricular hypertrophy - Dosing information - 150 mg/day[2], [3] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Irbesartan FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Irbesartan in pediatric patients. ### Non–Guideline-Supported Use ### Chronic Renal impairment - Dosing information - For those weighing 10 to 20 kilograms (kg): 37.5 mg/day - For those weighing 21 to 40 kg:75 mg/day - For those weighing over 40 kg: 150 mg/day [4] - For those weighing 35 kilograms (kg) or less: 75 mg/day - For those above 35 kg: 150 mg PO qd [5] # Contraindications Irbesartan is contraindicated in patients who are hypersensitive to any component of this product. Do not coadminister aliskiren with Irbesartan in patients with diabetes. # Warnings ### Pregnancy Category D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Irbesartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Irbesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Irbesartan for hypotension, oliguria, and hyperkalemia. - When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, and 650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses ≥50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body surface area basis). Subcutaneous edema was observed in fetuses at doses ≥180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits. - Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan. ### Hypotension in Volume- or Salt-Depleted Patients - Excessive reduction of blood pressure was rarely seen (<0.1%) in patients with uncomplicated hypertension. Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, eg, in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should be corrected prior to administration of Irbesartan, or a low starting dose should be used. - If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. ## PRECAUTIONS ### Impaired Renal Function - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure), treatment with angiotensin-converting-enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Irbesartan would be expected to behave similarly. - In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. There has been no known use of Irbesartan in patients with unilateral or bilateral renal artery stenosis, but a similar effect should be anticipated. ### Information for Patients - Female patients of childbearing age should be told about the consequences of exposure to Irbesartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. # Adverse Reactions ## Clinical Trials Experience ## Hypertension - Irbesartan has been evaluated for safety in more than 4300 patients with hypertension and about 5000 subjects overall. This experience includes 1303 patients treated for over 6 months and 407 patients for 1 year or more. Treatment with Irbesartan was well-tolerated, with an incidence of adverse events similar to placebo. These events generally were mild and transient with no relationship to the dose of Irbesartan. - In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event was required in 3.3% of patients treated with Irbesartan, versus 4.5% of patients given placebo. - In placebo-controlled clinical trials, the following adverse event experiences reported in at least 1% of patients treated with Irbesartan (n=1965) and at a higher incidence versus placebo (n=641), excluding those too general to be informative and those not reasonably associated with the use of drug because they were associated with the condition being treated or are very common in the treated population, include: diarrhea (3% vs 2%), dyspepsia/heartburn (2% vs 1%), and fatigue (4% vs 3%). - The following adverse events occurred at an incidence of 1% or greater in patients treated with irbesartan, but were at least as frequent or more frequent in patients receiving placebo: abdominal pain, anxiety/nervousness, chest pain, dizziness, edema, headache, influenza, musculoskeletal pain, pharyngitis, nausea/vomiting, rash, rhinitis, sinus abnormality, tachycardia, and urinary tract infection. - Irbesartan use was not associated with an increased incidence of dry cough, as is typically associated with ACE inhibitor use. In placebo-controlled studies, the incidence of cough in irbesartan-treated patients was 2.8% versus 2.7% in patients receiving placebo. - The incidence of hypotension or orthostatic hypotension was low in irbesartan- treated patients (0.4%), unrelated to dosage, and similar to the incidence among placebo-treated patients (0.2%). Dizziness, syncope, and vertigo were reported with equal or less frequency in patients receiving irbesartan compared with placebo. - In addition, the following potentially important events occurred in less than 1% of the 1965 patients and at least 5 patients (0.3%) receiving irbesartan in clinical studies, and those less frequent, clinically significant events (listed by body system). It cannot be determined whether these events were causally related to irbesartan: Body as a Whole: fever, chills, facial edema, upper extremity edema Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, arrhythmic/conduction disorder, cardio-respiratory arrest, heart failure, hypertensive crisis Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout Gastrointestinal: constipation, oral lesion, gastroenteritis, flatulence, abdominal distention Musculoskeletal/Connective Tissue: extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness Nervous System: sleep disturbance, numbness, somnolence, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident Renal/Genitourinary: abnormal urination, prostate disorder Respiratory: epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis, other eye disturbance, eyelid abnormality, ear abnormality ## Nephropathy in Type 2 Diabetic Patients - In clinical studies in patients with hypertension and type 2 diabetic renal disease, the adverse drug experiences were similar to those seen in patients with hypertension with the exception of an increased incidence of orthostatic symptoms (dizziness, orthostatic dizziness, and orthostatic hypotension) observed in IDNT (proteinuria ≥900 mg/day, and serum creatinine ranging from 1.0–3.0 mg/dL). In this trial, orthostatic symptoms occurred more frequently in the Irbesartan group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatic hypotension 5.4%) than in the placebo group (dizziness 6.0%, orthostatic dizziness 2.7%, orthostatic hypotension 3.2%). ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Irbesartan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Irbesartan. - The following have been reported: urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); increased liver function tests; jaundice; hepatitis; hyperkalemia, and thrombocytopenia. - Impaired renal function, including cases of renal failure, has been reported. - Cases of increased CPK and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. ## Laboratory Test Findings ### Hypertension - In controlled clinical trials, clinically important differences in laboratory tests were rarely associated with administration of Irbesartan. ### Creatinine, Blood Urea Nitrogen - Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.7% of patients with essential hypertension treated with Irbesartan alone versus 0.9% on placebo. ### Hematologic - Mean decreases in hemoglobin of 0.2 g/dL were observed in 0.2% of patients receiving Irbesartan compared to 0.3% of placebo-treated patients. Neutropenia (<1000 cells/mm3) occurred at similar frequencies among patients receiving Irbesartan (0.3%) and placebo-treated patients (0.5%). - Nephropathy in Type 2 Diabetic Patients ### Hyperkalemia - In IDNT (proteinuria ≥900 mg/day, and serum creatinine ranging from 1.0–3.0 mg/dL), the percent of patients with hyperkalemia (>6 mEq/L) was 18.6% in the Irbesartan group versus 6.0% in the placebo group. Discontinuations due to hyperkalemia in the Irbesartan group were 2.1% versus 0.4% in the placebo group. # Drug Interactions - No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine. - In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP 2C9 substrates/inhibitors sulphenazole, tolbutamide and nifedipine. However, in clinical studies the consequences of concomitant irbesartan on the pharmacodynamics of warfarin were negligible. Based on in vitrodata, no interaction would be expected with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4. - In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days had no effect on the pharmacodynamics of warfarin prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were not affected by coadministration of nifedipine or hydrochlorothiazide. - Concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. - Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including irbesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving irbesartan and NSAID therapy. - The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors. - Dual Blockade of the Renin-Angiotensin System (RAS) - Dual blockade of the RAS with angiotensin-receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on Irbesartan and other agents that affect the RAS. - Do not coadminister aliskiren with Irbesartan in patients with diabetes. Avoid use of aliskiren with Irbesartan in patients with renal impairment (GFR <60 mL/min). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Irbesartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Irbesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Irbesartan for hypotension, oliguria, and hyperkalemia. - When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, and 650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses ≥50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body surface area basis). Subcutaneous edema was observed in fetuses at doses ≥180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits. - Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Irbesartan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Irbesartan during labor and delivery. ### Nursing Mothers - It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Neonates with a history of in utero exposure to irbesartan: - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. - Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to 16 years. - Irbesartan has not been studied in pediatric patients less than 6 years old. ### Geriatic Use - Of 4925 subjects receiving irbesartan in controlled clinical studies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3.0%) were 75 years and over. No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations, and Clinical Studies). ### Gender There is no FDA guidance on the use of Irbesartan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Irbesartan with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Irbesartan in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Irbesartan in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Irbesartan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Irbesartan in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring FDA Package Insert for Irbesartan contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - No data are available in regard to overdosage in humans. However, daily doses of 900 mg for 8 weeks were well-tolerated. The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. Irbesartan is not removed by hemodialysis. - To obtain up-to-date information about the treatment of overdosage, a good resource is a certified regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians' Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug interactions, drug-drug interactions, and unusual drug kinetics in the patient. - Laboratory determinations of serum levels of irbesartan are not widely available, and such determinations have, in any event, no known established role in the management of irbesartan overdose. - Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25- and 50-fold the MRHD (300 mg) on a mg/m2 basis, respectively. # Pharmacology ## Mechanism of Action - Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system (RAS) and also stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor. There is also an AT2 receptor in many tissues, but it is not involved in cardiovascular homeostasis. Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (more than 8500 fold) for the AT1 receptor than for the AT2 receptor and no agonist activity. - Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure. - Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Because irbesartan does not inhibit ACE, it does not affect the response to bradykinin; whether this has clinical relevance is not known. ## Structure - Irbesartan®* (irbesartan) is an angiotensin II receptor (AT1 subtype) antagonist. - Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one. - Its empirical formula is C25H28N6O, and the structural formula: - Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water. ## Pharmacodynamics - In healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions. Inhibition was complete (100%) 4 hours following oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours (60% and 40% at 300 mg and 150 mg, respectively). - In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan causes a 1.5- to 2-fold rise in angiotensin II plasma concentration and a 2- to 3-fold increase in plasma renin levels. Aldosterone plasma concentrations generally decline following irbesartan administration, but serum potassium levels are not significantly affected at recommended doses. - In hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had no effect on glomerular filtration rate, renal plasma flow, or filtration fraction. In multiple dose studies in hypertensive patients, there were no clinically important effects on fasting triglycerides, total cholesterol, HDL-cholesterol, or fasting glucose concentrations. There was no effect on serum uric acid during chronic oral administration, and no uricosuric effect. ## Pharmacokinetics Irbesartan is an orally active agent that does not require biotransformation into an active form. The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% to 80%. Following oral administration of Irbesartan, peak plasma concentrations of irbesartan are attained at 1.5 to 2 hours after dosing. Food does not affect the bioavailability of Irbesartan. - Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range. - The terminal elimination half-life of irbesartan averaged 11 to 15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing. ## Metabolism and Elimination - Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of 14C-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to irbesartan's pharmacologic activity. - Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of 14C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide. - In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4. ## Distribution - Irbesartan is 90% bound to serum proteins (primarily albumin and α1-acid glycoprotein) with negligible binding to cellular components of blood. The average volume of distribution is 53 liters to 93 liters. Total plasma and renal clearances are in the range of 157 mL/min to 176 mL/min and 3.0 mL/min to 3.5 mL/min, respectively. With repetitive dosing, irbesartan accumulates to no clinically relevant extent. - Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta. Irbesartan is excreted in the milk of lactating rats. ## Special Populations ### Gender - No gender-related differences in pharmacokinetics were observed in healthy elderly (age 65–80 years) or in healthy young (age 18–40 years) subjects. In studies of hypertensive patients, there was no gender difference in half-life or accumulation, but somewhat higher plasma concentrations of irbesartan were observed in females (11–44%). No gender-related dosage adjustment is necessary. ### Geriatric - In elderly subjects (age 65–80 years), irbesartan elimination half-life was not significantly altered, but AUC and Cmax values were about 20% to 50% greater than those of young subjects (age 18–40 years). No dosage adjustment is necessary in the elderly. ### Race - In healthy black subjects, irbesartan AUC values were approximately 25% greater than whites; there were no differences in Cmax values. ### Renal Insufficiency - The pharmacokinetics of irbesartan were not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted. ### Hepatic Insufficiency - The pharmacokinetics of irbesartan following repeated oral administration were not significantly affected in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500/1000 mg/kg/day (males/females, respectively) in rats and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500 mg/kg/day provided an average systemic exposure to irbesartan (AUC0–24 hour, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure in humans receiving the maximum recommended dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to females only) provided an average systemic exposure about 21 times that reported for humans at the MRD. For male and female mice, 1000 mg/kg/day provided an exposure to irbesartan about 3 and 5 times, respectively, the human exposure at 300 mg/day. - Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro-human lymphocyte assay; in vivo-mouse micronucleus study). - Irbesartan had no adverse effects on fertility or mating of male or female rats at oral doses ≤650 mg/kg/day, the highest dose providing a systemic exposure to irbesartan (AUC0–24 hour, bound plus unbound) about 5 times that found in humans receiving the maximum recommended dose of 300 mg/day. # Clinical Studies ## Hypertension - The antihypertensive effects of Irbesartan (irbesartan) were examined in 7 major placebo-controlled 8 to 12 week trials in patients with baseline diastolic blood pressures of 95 mmHg to 110 mmHg. Doses of 1 mg to 900 mg were included in these trials in order to fully explore the dose-range of irbesartan. These studies allowed comparison of once- or twice-daily regimens at 150 mg/day, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Two of the 7 placebo-controlled trials identified above examined the antihypertensive effects of irbesartan and hydrochlorothiazide in combination. - The 7 studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan (1–900 mg) and 611 patients randomized to placebo. Once-daily doses of 150 mg and 300 mg provided statistically and clinically significant decreases in systolic and diastolic blood pressure with trough (24 hours post-dose) effects after 6 to 12 weeks of treatment compared to placebo, of about 8–10/5–6 mmHg and 8–12/5–8 mmHg, respectively. No further increase in effect was seen at dosages greater than 300 mg. The dose-response relationships for effects on systolic and diastolic pressure are shown in Figures 1 and 2. - Once-daily administration of therapeutic doses of irbesartan gave peak effects at around 3 to 6 hours and, in one ambulatory blood pressure monitoring study, again around 14 hours. This was seen with both once-daily and twice-daily dosing. Trough-to-peak ratios for systolic and diastolic response were generally between 60% to 70%. In a continuous ambulatory blood pressure monitoring study, once-daily dosing with 150 mg gave trough and mean 24-hour responses similar to those observed in patients receiving twice-daily dosing at the same total daily dose. - In controlled trials, the addition of irbesartan to hydrochlorothiazidedoses of 6.25 mg, 12.5 mg, or 25 mg produced further dose-related reductions in blood pressure similar to those achieved with the same monotherapy dose of irbesartan. HCTZ also had an approximately additive effect. - Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65 years of age, had generally similar responses. Irbesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population). - The effect of irbesartan is apparent after the first dose, and it is close to its full observed effect at 2 weeks. At the end of an 8-week exposure, about 2/3 of the antihypertensive effect was still present one week after the last dose. Rebound hypertension was not observed. There was essentially no change in average heart rate in irbesartan-treated patients in controlled trials. ## Nephropathy in Type 2 Diabetic Patients - The Irbesartan Diabetic Nephropathy Trial (IDNT) was a randomized, placebo- and active-controlled, double-blind, multicenter study conducted worldwide in 1715 patients with type 2 diabetes, hypertension (SeSBP >135 mmHg or SeDBP >85 mmHg), and nephropathy (serum creatinine 1.0 to 3.0 mg/dL in females or 1.2 to 3.0 mg/dL in males and proteinuria ≥900 mg/day). Patients were randomized to receive Irbesartan 75 mg, amlodipine 2.5 mg, or matching placebo once-daily. Patients were titrated to a maintenance dose of Irbesartan 300 mg, or amlodipine 10 mg, as tolerated. Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and calcium channel blockers) were added as needed to achieve blood pressure goal (≤135/85 or 10 mmHg reduction in systolic blood pressure if higher than 160 mmHg) for patients in all groups. - The study population was 66.5% male, 72.9% below 65 years of age and 72% White, (Asian/Pacific Islander 5.0%, Black 13.3%, Hispanic 4.8%). The mean baseline seated systolic and diastolic blood pressures were 159 mmHg and 87 mmHg, respectively. The patients entered the trial with a mean serum creatinine of 1.7 mg/dL and mean proteinuria of 4144 mg/day. - The mean blood pressure achieved was 142/77 mmHg for Irbesartan, 142/76 mmHg for amlodipine, and 145/79 mmHg for placebo. Overall, 83.0% of patients received the target dose of irbesartan more than 50% of the time. Patients were followed for a mean duration of 2.6 years. - The primary composite endpoint was the time to occurrence of any one of the following events: doubling of baseline serum creatinine, end-stage renal disease (ESRD; defined by serum creatinine ≥6 mg/dL, dialysis, or renal transplantation) or death. Treatment with Irbesartan resulted in a 20% risk reduction versus placebo (p=0.0234) (see Figure 3 and Table 1). Treatment with Irbesartan also reduced the occurrence of sustained doubling of serum creatinine as a separate endpoint (33%), but had no significant effect on ESRD alone and no effect on overall mortality (see Table 1). - The percentages of patients experiencing an event during the course of the study can be seen in Table 1 below: - The secondary endpoint of the study was a composite of cardiovascular mortality and morbidity (myocardial infarction, hospitalization for heart failure, stroke with permanent neurological deficit, amputation). There were no statistically significant differences among treatment groups in these endpoints. Compared with placebo, Irbesartan significantly reduced proteinuria by about 27%, an effect that was evident within 3 months of starting therapy. Irbesartan significantly reduced the rate of loss of renal function (glomerular filtration rate), as measured by the reciprocal of the serum creatinine concentration, by 18.2%. - Table 2 presents results for demographic subgroups. Subgroup analyses are difficult to interpret and it is not known whether these observations represent true differences or chance effects. For the primary endpoint, Irbesartan's favorable effects were seen in patients also taking other antihypertensive medications (angiotensin II receptor antagonists, angiotensin-converting-enzyme inhibitors and calcium channel blockers were not allowed), oral hypoglycemic agents, and lipid-lowering agents. # How Supplied - Irbesartan tablets USP are available as follows: ## Storage - Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. - Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Pregnancy - Female patients of childbearing age should be told about the consequences of exposure to irbesartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. # Precautions with Alcohol Alcohol-Irbesartan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Avapro # Look-Alike Drug Names There is limited information about the Look-Alike Drug Names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Avalide
1ec18149586e9341c7645cff63f6e81ee1b804ef	wikidoc	Avermectin	Avermectin Avermectin is a family of anti-parasitic drugs whose analogues include ivermectin, selamectin, doramectin and abamectin. # Avermectin therapy for rodent fur mite infestation A commonly used therapy in recent times has been based on oral or parenteral administration of avermectins, which are macrocyclic lactones produced by fermentation of the soil micro-organism Streptomyces avermitilis. They show activity against a broad range of nematodes and arthropod parasites of domestic animals at dose rates of 300 microgram/kg or less. Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activity (Hotson, 1982). Avermectin therapy is not without its drawbacks. Resistance to avermectins has been reported, which suggests use in moderation (Clark, 1995). Research on ivermectin, piperazine, and dichlorvos in combinations also shows potential for toxicity (Toth, 2000). Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor, nitric oxide, prostaglandin E2, and increase of intracellular concentration of Ca2+ (Victorov, 2003). A proven ectoparasite mitigation method that stresses lab animals less than avermectin oral administration is definitely desirable. Permethrin based treatments such as MiteArrest may be a viable alternative.	Avermectin Avermectin is a family of anti-parasitic drugs whose analogues include ivermectin, selamectin, doramectin and abamectin. # Avermectin therapy for rodent fur mite infestation A commonly used therapy in recent times has been based on oral or parenteral administration of avermectins, which are macrocyclic lactones produced by fermentation of the soil micro-organism Streptomyces avermitilis. They show activity against a broad range of nematodes and arthropod parasites of domestic animals at dose rates of 300 microgram/kg or less. Unlike the macrolide or polyene antibiotics, they lack significant antibacterial or antifungal activity (Hotson, 1982). Avermectin therapy is not without its drawbacks. Resistance to avermectins has been reported, which suggests use in moderation (Clark, 1995). Research on ivermectin, piperazine, and dichlorvos in combinations also shows potential for toxicity (Toth, 2000). Avermectin has been reported to block LPS-induced secretion of tumor necrosis factor, nitric oxide, prostaglandin E2, and increase of intracellular concentration of Ca2+ (Victorov, 2003). A proven ectoparasite mitigation method that stresses lab animals less than avermectin oral administration is definitely desirable. Permethrin based treatments such as MiteArrest may be a viable alternative.	https://www.wikidoc.org/index.php/Avermectin
fd8b0b7ac38514a3f1ddd9d2897823a6c2a619db	wikidoc	Avobenzone	Avobenzone Avobenzone (trade names Parsol® 1789, Eusolex® 9020, Escalol® 517 and others, INCI Butyl Methoxydibenzoylmethane) is an oil soluble ingredient used in sunscreen products to absorb the full spectrum of UVA rays. It is a dibenzoylmethane derivative. Its ability to absorb ultraviolet light over a wider range of wavelengths than many organic sunscreen agents has led to its use in many commercial preparations marketed as "broad spectrum" sunscreens. Avobenzone was patented in 1973 and was approved in the EU in 1978. It was approved by the FDA in 1988. Its use is approved world wide. Avobenzone has been shown to degrade significantly in light, resulting in less protection over time. The UV-A light in a day of sunlight in a temperate climate is sufficient to break down most of the compound. This degradation can be reduced by using a photostabilizer, like octocrylene. Other photostabilizers include: - 4-Methylbenzylidene camphor (USAN Enzacamene) - Tinosorb® S (USAN Bemotrizinol, INCI Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine) - Tinosorb® M (USAN Bisoctrizole, INCI Methylene Bis-Benzotriazolyl Tetramethylbutylphenol) - Butyloctyl Salicylate - Hexadecyl Benzoate - Butyloctyl Benzoate - Mexoryl® SX (USAN Ecamsule, INCI Terephthalylidene Dicamphor Sulfonic Acid) - Corapan® TQ (INCI Diethylhexyl 2,6-Naphthalate) - Parsol® SLX (INCI Polysilicone-15) - Oxynex® ST (INCI Diethylhexyl Syringylidene Malonate) Complexing avobenzone with cyclodextrins may also increase its photostability. According to some studies, "the most effective sunscreens contain avobenzone and titanium dioxide." The combination with TiO2 is approved for use in the EU, but in the US the FDA has yet to approve this, stating (in 1997) that "until complete and adequate data have been submitted, the agency has no basis to allow other avobenzone combinations" (containing titanium dioxide).(this is wrong) Avobenzone can degrade faster in light in combination with mineral UV absorbers like zinc oxide and titanium dioxide, though with the right coating of the mineral particles this reaction can be reduced. A manganese doped titanium dioxide may be better than undoped titanium dioxide to improve avobenzone's stability. Avobenzone reacts with minerals to form colored complexes. Manufacturers of avobenzone, like DSM recommend to include a chelator to prevent this from happening. They also recommend to avoid the inclusion of iron and ferric salts, heavy metals, formaldehyde donors and PABA and PABA esters. The makers of Coppertone advise that avobenzone binds iron and can cause staining of clothes washed in iron-rich water.	Avobenzone Template:OrganicBox small Avobenzone (trade names Parsol® 1789, Eusolex® 9020, Escalol® 517 and others, INCI Butyl Methoxydibenzoylmethane) is an oil soluble ingredient used in sunscreen products to absorb the full spectrum of UVA rays. It is a dibenzoylmethane derivative. Its ability to absorb ultraviolet light over a wider range of wavelengths than many organic sunscreen agents has led to its use in many commercial preparations marketed as "broad spectrum" sunscreens. Avobenzone was patented in 1973 and was approved in the EU in 1978. It was approved by the FDA in 1988. Its use is approved world wide. Avobenzone has been shown to degrade significantly in light, resulting in less protection over time.[1][2][3] The UV-A light in a day of sunlight in a temperate climate is sufficient to break down most of the compound. This degradation can be reduced by using a photostabilizer, like octocrylene. Other photostabilizers include: - 4-Methylbenzylidene camphor (USAN Enzacamene) - Tinosorb® S (USAN Bemotrizinol, INCI Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine) - Tinosorb® M (USAN Bisoctrizole, INCI Methylene Bis-Benzotriazolyl Tetramethylbutylphenol) - Butyloctyl Salicylate - Hexadecyl Benzoate - Butyloctyl Benzoate - Mexoryl® SX (USAN Ecamsule, INCI Terephthalylidene Dicamphor Sulfonic Acid) - Corapan® TQ (INCI Diethylhexyl 2,6-Naphthalate)[4] - Parsol® SLX (INCI Polysilicone-15) - Oxynex® ST (INCI Diethylhexyl Syringylidene Malonate)[5] Complexing avobenzone with cyclodextrins may also increase its photostability.[6] According to some studies, "the most effective sunscreens contain avobenzone and titanium dioxide." [7] The combination with TiO2 is approved for use in the EU, but in the US the FDA has yet to approve this, stating (in 1997) that "until complete and adequate data have been submitted, the agency has no basis to allow other avobenzone combinations" (containing titanium dioxide).(this is wrong)[8][9] Avobenzone can degrade faster in light in combination with mineral UV absorbers like zinc oxide and titanium dioxide, though with the right coating of the mineral particles this reaction can be reduced.[10] A manganese doped titanium dioxide may be better than undoped titanium dioxide to improve avobenzone's stability.[11] Avobenzone reacts with minerals to form colored complexes. Manufacturers of avobenzone, like DSM recommend to include a chelator to prevent this from happening. They also recommend to avoid the inclusion of iron and ferric salts, heavy metals, formaldehyde donors and PABA and PABA esters. The makers of Coppertone advise that avobenzone binds iron and can cause staining of clothes washed in iron-rich water.	https://www.wikidoc.org/index.php/Avobenzone
88cb35dc0a0e809ddf6c8ac203fcf546aea72bae	wikidoc	Rasagiline	Rasagiline # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Rasagiline is a monoamine oxidase (MAO)-B inhibitor (MAOI) that is FDA approved for the {{{indicationType}}} of parkinson’s disease. Common adverse reactions include flu syndrome, arthralgia, depression, and dyspepsia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - When AZILECT is prescribed as monotherapy or as adjunct therapy in patients not taking levodopa, patients may start AZILECT at the recommended dose of 1 mg administered orally once daily. - In patients taking levodopa, with or without other PD drugs (e.g., dopamine agonist, amantadine, anticholinergics), the recommended initial dose of AZILECT is 0.5 mg once daily. If the patient tolerates the daily 0.5 mg dose, but a sufficient clinical response is not achieved, the dose may be increased to 1 mg once daily. When AZILECT is used in combination with levodopa, a reduction of the levodopa dose may be considered, based upon individual response. - The recommended doses of AZILECT should not be exceeded because of risk of hypertension. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rasagiline in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasagiline in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Rasagiline in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rasagiline in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasagiline in pediatric patients. # Contraindications - AZILECT is contraindicated for use with meperidine, tramadol, methadone, propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors, because of risk of serotonin syndrome. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with these medications. - AZILECT is contraindicated for use with St. John’s wort and with cyclobenzaprine. - AZILECT is contraindicated for use with dextromethorphan because of risk of episode of psychosis or bizarre behavior. # Warnings ### Precautions - Hypertension - Exacerbation of hypertension may occur during treatment with AZILECT. Medication adjustment may be necessary if elevation of blood pressure is sustained. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting AZILECT. - In Study 3, AZILECT (1 mg/day) given in conjunction with levodopa, produced an increased incidence of significant blood pressure elevation (systolic > 180 or diastolic > 100 mm Hg) of 4% compared to 3% for placebo . - When used as an adjunct to levodopa (Studies 3 and 4), the risk for developing post-treatment high blood pressure (e.g., systolic > 180 or diastolic >100 mm Hg) combined with a significant increase from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for AZILECT (2%) compared to placebo (1%). - Dietary tyramine restriction is not required during treatment with recommended doses of AZILECT. However, certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine that could potentially cause severe hypertension because of tyramine interaction (including various clinical syndromes referred to as hypertensive urgency, crisis, or emergency) in patients taking AZILECT, even at the recommended doses, due to increased sensitivity to tyramine. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of AZILECT because of the potential for large increases in blood pressure including clinical syndromes referred to as hypertensive urgency, crisis, or emergency. AZILECT is a selective inhibitor of MAO-B at the recommended doses of 0.5 or 1 mg daily. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses. - Serotonin Syndrome - Serotonin syndrome has been reported with concomitant use of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a nonselective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (AZILECT). Serotonin syndrome has also been reported with concomitant use of AZILECT with meperidine, tramadol, methadone, or propoxyphene. AZILECT is contraindicated for use with meperidine, tramadol, methadone, propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors. - In the postmarketing period, potentially life-threatening serotonin syndrome has been reported in patients treated with antidepressants concomitantly with AZILECT. Concomitant use of AZILECT with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommende. - The symptoms of serotonin syndrome have included behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor). Serotonin syndrome can result in death. - AZILECT clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with AZILECT, and the potential drug interaction between AZILECT and antidepressants has not been studied systematically. Although a small number of AZILECT-treated patients were concomitantly exposed to antidepressants (tricyclics n=115; SSRIs n=141), the exposure, both in dose and number of subjects, was not adequate to rule out the possibility of an untoward reaction from combining these agents. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. Because of the long half-lives of certain antidepressants (e.g., fluoxetine and its active metabolite), at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of AZILECT. - Falling Asleep During Activities of Daily Living and Somnolence - It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should monitor patients for drowsiness or sleepiness, because some of the events occur well after initiation of treatment with dopaminergic medication. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. - Cases of patients treated with AZILECT and other dopaminergic medications have reported falling asleep while engaged in activities of daily living including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on AZILECT with other dopaminergic medications, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1-year after initiation of treatment. - In Study 3, somnolence was a common occurrence in patients receiving AZILECT and was more frequent in patients with Parkinson’s disease receiving AZILECT than in respective patients receiving placebo (6% AZILECT compared to 4% Placebo). - Before initiating treatment with AZILECT, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with AZILECT such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase rasagiline plasma levels (e.g., ciprofloxacin). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), AZILECT should ordinarily be discontinued. If a decision is made to continue these patients on AZILECT, advise them to avoid driving and other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. - Ciprofloxacin or Other CYP1A2 Inhibitors - Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily. - Hepatic Impairment - Rasagiline plasma concentration may increase in patients with hepatic impairment. Patients with mild hepatic impairment should be given the dose of AZILECT 0.5 mg once daily. AZILECT should not be used in patients with moderate or severe hepatic impairment. - Hypotension / Orthostatic Hypotension - In Study 3, the incidence of orthostatic hypotension consisting of a systolic blood pressure decrease (≥ 30 mm Hg) or a diastolic blood pressure decrease (> 20 mm Hg) after standing was 13% with AZILECT (1 mg/day) compared to 9% with placebo. - At the 1 mg dose, the frequency of orthostatic hypotension (at any time during the study) was approximately 44% for AZILECT vs 33% for placebo for mild to moderate systolic blood pressure decrements (> 20 mm Hg), 40% for AZILECT vs 33% for placebo for mild to moderate diastolic blood pressure decrements (> 10 mm Hg), 7% for AZILECT vs 3% for placebo for severe systolic blood pressure decrements (> 40 mm Hg), and 9% for AZILECT vs 6% for placebo for severe diastolic blood pressure decrements (≥ 20 mm Hg). There was also an increased risk for some of these abnormalities at the lower 0.5 mg daily dose and for an individual patient having mild to moderate or severe orthostatic hypotension for both systolic and diastolic blood pressure. - In Study 2 where AZILECT was given as an adjunct therapy in patients not taking concomitant levodopa, there were 5 reports of orthostatic hypotension in patients taking AZILECT 1 mg (3.1%) and 1 report in patients taking placebo (0.6%). - Clinical trial data further suggest that orthostatic hypotension occurs most frequently in the first two months of AZILECT treatment and tends to decrease over time. - Some patients treated with AZILECT experienced a mildly increased risk for significant decreases in blood pressure unrelated to standing but while supine. - The risk for post-treatment hypotension (e.g., systolic 30 or diastolic > 20 mm Hg) was higher for AZILECT 1 mg (3.2%) compared to placebo (1.3%). - There was no clear increased risk for lowering of blood pressure or postural hypotension associated with AZILECT 1 mg/day as monotherapy. - When used as an adjunct to levodopa, postural hypotension was also reported as an adverse reaction in approximately 6% of patients treated with AZILECT 0.5 mg, 9% of patients treated with AZILECT 1 mg and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with AZILECT 1 mg/day, no patients treated with AZILECT 0.5 mg/day and no placebo-treated patients. - Dyskinesia - When used as an adjunct to levodopa, AZILECT may cause dyskinesia or potentiate dopaminergic side effects and exacerbate pre-existing dyskinesia. In Study 3, the incidence of dyskinesia was 18% for patients treated with 0.5 mg or 1 mg AZILECT as an adjunct to levodopa and 10% for patients treated with placebo as an adjunct to levodopa. Decreasing the dose of levodopa may mitigate this side effect. - Hallucinations / Psychotic-Like Behavior - In the monotherapy study (Study 1), the incidence of hallucinations reported as an adverse event was 1.3% in patients treated with AZILECT 1 mg and 0.7% in patients treated with placebo. In Study 1, the incidence of hallucinations reported as an adverse reaction and leading to drug discontinuation and premature withdrawal was 1.3% in patients treated with AZILECT 1 mg and 0% in placebo-treated patients. - When studied as an adjunct therapy without levodopa (Study 2), hallucinations were reported as an adverse reaction in 1.2% of patients treated with 1 mg/day AZILECT and 1.8% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from the clinical trial in 0.6% of patients treated with AZILECT 1 mg/day and in none of the placebo-treated patients. - When studied as an adjunct to levodopa (Study 3), the incidence of hallucinations was approximately 5% in patients treated with AZILECT 0.5 mg/day, 4% in patients treated with AZILECT 1 mg/day, and 3% in patients treated with placebo. The incidence of hallucinations leading to drug discontinuation and premature withdrawal was about 1% in patients treated with 0.5 mg AZILECT and 1 mg AZILECT/day, and 0% in placebo-treated patients. - Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with AZILECT or after starting or increasing the dose of AZILECT. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. - Patients should be informed of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop. - Patients with a major psychotic disorder should ordinarily not be treated with AZILECT because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, many treatments for psychosis that decrease central dopaminergic tone may decrease the effectiveness of AZILECT. - Consider dose reduction or stopping the medication if a patient develops hallucinations or psychotic like behaviors while taking AZILECT. - Impulse Control / Compulsive Behaviors - Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including AZILECT, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with AZILECT. Consider dose reduction or stopping the medication if a patient develops such urges while taking AZILECT. - Withdrawal-Emergent Hyperpyrexia and Confusion - A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. - Melanoma - Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. - For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the rates of adverse reactions observed in practice. - During the clinical development of AZILECT, Parkinson’s disease patients received AZILECT as initial monotherapy (Study 1) and as adjunct therapy (Study 2, Study 3, Study 4). As the populations in these studies differ, not only in the adjunct use of dopamine agonists or levodopa during AZILECT treatment, but also in the severity and duration of their disease, the adverse reactions are presented separately for each study. - Monotherapy Use of AZILECT - In Study 1, approximately 5% of the 149 patients treated with AZILECT discontinued treatment due to adverse reactions compared to 2% of the 151 patients who received placebo. - The only adverse reaction that led to the discontinuation of more than one patient was hallucinations. - The most commonly observed adverse reactions in Study 1 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists adverse reactions that occurred in 2% or greater of patients receiving AZILECT as monotherapy and were numerically more frequent than in the placebo group in Study 1. - Adjunct Use of AZILECT - AZILECT was studied as an adjunct therapy without levodopa (Study 2), or as an adjunct therapy to levodopa, with some patients also taking dopamine agonists, COMT inhibitors, anticholinergics, or amantadine (Study 3 and Study 4). - In Study 2, approximately 8% of the 162 patients treated with AZILECT discontinued treatment due to adverse reactions compared to 4% of the 164 patients who received placebo. - Adverse reactions that led to the discontinuation of more than one patient were nausea and dizziness. - The most commonly observed adverse reactions in Study 2 (incidence in AZILECT-treated patients 3% or greater than incidence in placebo-treated patients) included peripheral edema, fall, arthralgia, cough, and insomnia. Table 2 lists adverse reactions that occurred in 2% or greater in patients receiving AZILECT as adjunct therapy without levodopa and numerically more frequent than in the placebo group in Study 2. - In Study 3, adverse event reporting was considered more reliable than Study 4; therefore, only the adverse event data from Study 3 are presented below. - In Study 3, approximately 9% of the 164 patients treated with AZILECT 0.5 mg/day and 7% of the 149 patients treated with AZILECT 1 mg/day discontinued treatment due to adverse reactions, compared to 6% of the 159 patients who received placebo. The adverse reactions that led to discontinuation of more than one AZILECT-treated patient were diarrhea, weight loss, hallucination, and rash. - The most commonly observed adverse reactions in Study 3 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, fall and tenosynovitis. - Table 3 lists adverse reactions that occurred in 2% or greater of patients treated with AZILECT 1 mg/day and that were numerically more frequent than the placebo group in Study 3. - Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth. - There were no significant differences in the safety profile based on age or gender. - During all Parkinson’s disease phase 2/3 clinical trials, the long-term safety profile was similar to that observed with shorter duration exposure. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Rasagiline in the drug label. # Drug Interactions - Meperidine - Serious, sometimes fatal reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors. - Dextromethorphan - The concomitant use of AZILECT and dextromethorphan was not allowed in clinical studies. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of AZILECT’s MAO inhibitory activity, dextromethorphan is contraindicated for use with AZILECT. - MAO Inhibitors - AZILECT is contraindicated for use with other MAO inhibitors because of the increased risk of nonselective MAO inhibition that may lead to a hypertensive crisis. - Sympathomimetic Medications - The concomitant use of AZILECT and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAO inhibitors. Hypertensive crisis has been reported in patients taking the recommended dose of AZILECT and sympathomimetic medications. Severe hypertension has been reported in patients taking the recommended dose of AZILECT and ophthalmic drops containing sympathomimetic medications. - Because AZILECT is a selective MAOI, hypertensive reactions are not ordinarily expected with the concomitant use of sympathomimetic medications. Nevertheless, caution should be exercised when concomitantly using recommended doses of AZILECT with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies. - Antidepressants - Concomitant use of AZILECT with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended. Concomitant use of AZILECT and MAO inhibitors is contraindicated. - Ciprofloxacin or Other CYP1A2 Inhibitors - Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. This could result in increased adverse events. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily. - Tyramine/Rasagiline Interaction - MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a tyramine reaction with hypertension including clinical syndromes referred to as hypertensive urgency, crisis, or emergency. Foods and medications containing large amounts of exogenous amines (e.g., from fermented cheese, herring, over-the-counter cough/cold medications) may cause release of norepinephrine resulting in a rise in systemic blood pressure. - Results of a special tyramine challenge study indicate that rasagiline is selective for MAO-B at recommended doses and can be used without dietary tyramine restriction. However, certain foods may contain very high amounts (i.e., 150 mg or greater) of tyramine and could potentially cause a hypertensive reaction in individual patients taking AZILECT due to increased sensitivity to tyramine. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses. - There were no cases of hypertensive crisis in the clinical development program associated with 1 mg daily AZILECT treatment, in which most patients did not follow dietary tyramine restriction. - There have been postmarketing reports of patients who experienced significantly elevated blood pressure (including rare cases of hypertensive crisis) after ingestion of unknown amounts of tyramine-rich foods while taking recommended doses of AZILECT. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of AZILECT. - Dopaminergic Antagonists - It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of AZILECT. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies of rasagiline in pregnant women. AZILECT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In a combined mating/fertility and embryo-fetal development study in pregnant rats, no effect on embryo-fetal development was observed at oral doses up to 3 mg/kg/day (approximately 30 times the plasma exposure (AUC) in humans at the maximum recommended human dose ). - In pregnant rabbits administered rasagiline throughout the period of organogenesis at oral doses of up to 36 mg/kg/day, no developmental toxicity was observed. At the highest dose tested, the plasma AUC was approximately 800 times that in humans at the MRHD. - In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) orally during gestation and lactation, offspring survival was decreased and offspring body weight was reduced at 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the plasma AUC in humans at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is similar to the MRHD on a mg/m2 basis. The effect of rasagiline on physical and behavioral development was not adequately assessed in this study. - Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) orally throughout the period of organogenesis, there was an increased incidence of wavy ribs in fetuses from rats treated with rasagiline in combination with levodopa/carbidopa at 1/80/20 mg/kg/day (approximately 8 times the rasagiline plasma AUC in humans at the MRHD and similar to the MRHD of levodopa/carbidopa on a mg/m2 basis). In pregnant rabbits dosed orally throughout the period of organogenesis with rasagiline alone (3 mg/kg) or in combination with levodopa/carbidopa (rasagiline: 0.1, 0.6, 1.2 mg/kg, levodopa/carbidopa: 80/20 mg/kg/day), an increase in embryo-fetal death was noted at rasagiline doses of 0.6 and 1.2 mg/kg/day when administered in combination with levodopa/carbidopa (approximately 7 and 13 times, respectively, the rasagiline plasma AUC in humans at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (similar to the MRHD on a mg/m2 basis) and to a greater extent when rasagiline (at all doses; 1-13 times the rasagiline plasma AUC in humans at the MRHD) was administered in combination with levodopa/carbidopa. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rasagiline in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Rasagiline during labor and delivery. ### Nursing Mothers - In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in humans. - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AZILECT is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Approximately half of patients in clinical trials were 65 years and over. There were no significant differences in the safety profile of the geriatric and nongeriatric patients. ### Gender There is no FDA guidance on the use of Rasagiline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Rasagiline with respect to specific racial populations. ### Renal Impairment - Dose adjustment of AZILECT is not required for patients with mild or moderate renal impairment because AZILECT plasma concentrations are not increased in patients with moderate renal impairment. Rasagiline has not been studied in patients with severe renal impairment. ### Hepatic Impairment - Rasagiline plasma concentration may be increased in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should not exceed a dose of 0.5 mg/day. AZILECT should not be used in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Rasagiline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Rasagiline in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Rasagiline in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Rasagiline in the drug label. # Overdosage ## Acute Overdose - In a dose escalation study in patients on chronic levodopa therapy treated with 10 mg of AZILECT there were three reports of cardiovascular side effects (including hypertension and postural hypotension) which resolved following treatment discontinuation. - Although no cases of overdose have been observed with AZILECT during the clinical development program, the following description of presenting symptoms and clinical course is based upon overdose descriptions of nonselective MAO inhibitors. - The signs and symptoms of nonselective MAOI overdose may not appear immediately. Delays of up to 12 hours after ingestion of drug and the appearance of signs may occur. The peak intensity of the syndrome may not be reached until for a day following the overdose. Death has been reported following overdose; therefore, immediate hospitalization, with continuous patient observation and monitoring for at least two days following the ingestion of such drugs in overdose, is strongly recommended. - The severity of the clinical signs and symptoms of MAOI overdose varies and may be related to the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved. - Signs and symptoms of MAOI overdose may include: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. - There is no specific antidote for AZILECT overdose. The following suggestions are offered based upon the assumption that AZILECT overdose may be modeled after nonselective MAO inhibitor poisoning. Treatment of overdose with nonselective MAO inhibitors is symptomatic and supportive. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential. For this reason, in cases of overdose with AZILECT, dietary tyramine restriction should be observed for several weeks to reduce the risk of hypertensive tyramine reaction. - A poison control center should be called for the most current treatment guidelines. - A postmarketing report described a single patient who developed a nonfatal serotonin syndrome after ingesting 100 mg of AZILECT in a suicide attempt. Another patient who was treated in error with 4 mg AZILECT daily and tramadol also developed a serotonin syndrome. One patient who was treated in error with 3 mg AZILECT daily experienced alternating episodes of vascular fluctuations consisting of hypertension and orthostatic hypotension. ## Chronic Overdose There is limited information regarding Chronic Overdose of Rasagiline in the drug label. # Pharmacology ## Mechanism of Action - AZILECT is a selective, irreversible MAO-B inhibitor indicated for the treatment of idiopathic Parkinson’s disease. The results of a clinical trial designed to examine the effects of AZILECT on blood pressure when it is administered with increasing doses of tyramine indicates the functional selectivity can be incomplete when healthy subjects ingest large amounts of tyramine while receiving recommended doses of AZILECT. The selectivity for inhibiting MAO-B diminishes in a dose-related manner. - MAO, a flavin-containing enzyme, is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. MAO-B is the major form in the human brain. In ex vivo animal studies in brain, liver, and intestinal tissues, rasagiline was shown to be a potent, irreversible monoamine oxidase type B (MAO-B) selective inhibitor. Rasagiline at the recommended therapeutic dose was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The precise mechanisms of action of rasagiline are unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline’s beneficial effects seen in models of dopaminergic motor dysfunction. ## Structure - AZILECT® tablets contain rasagiline (as the mesylate), a propargylamine-based drug indicated for the treatment of idiopathic Parkinson’s disease. It is designated chemically as: 1H-Inden-1-amine, 2, 3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate. The empirical formula of rasagiline mesylate is (C12H13N)CH4SO3 and its molecular weight is 267.34. - Its structural formula is: - Rasagiline mesylate is a white to off-white powder, freely soluble in water or ethanol and sparingly soluble in isopropanol. Each AZILECT tablet for oral administration contains rasagiline mesylate equivalent to 0.5 mg or 1 mg of rasagiline base. - Each AZILECT tablet also contains the following inactive ingredients: mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid and talc. ## Pharmacodynamics - Tyramine Challenge Test - Results of a tyramine challenge study indicate that rasagiline at recommended doses is relatively selective for inhibiting MAO-B and can be used without dietary tyramine restriction. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts of tyramine (i.e., 150 mg or greater) and could potentially cause severe hypertension caused by tyramine interaction in patients taking AZILECT due to mild increased sensitivity to tyramine at recommended doses. Relative selectivity of AZILECT for inhibiting MAO-B diminished in a dose-related manner as the dose progressively increased above the highest recommended daily dose (1 mg). - Platelet MAO Activity in Clinical Studies - Studies in healthy subjects and in Parkinson’s disease patients have shown that rasagiline inhibits platelet MAO-B irreversibly. The inhibition lasts at least 1 week after last dose. Almost 25-35% MAO-B inhibition was achieved after a single rasagiline dose of 1 mg/day and more than 55% of MAO-B inhibition was achieved after a single rasagiline dose of 2 mg/day. Over 90% inhibition was achieved 3 days after rasagiline daily dosing at 2 mg/day and this inhibition level was maintained 3 days postdose. Multiple doses of rasagiline of 0.5, 1 and 2 mg per day resulted in complete MAO-B inhibition. ## Pharmacokinetics - Rasagiline in the range of 1-6 mg demonstrated a more than proportional increase in AUC, while Cmax was dose proportional. Rasagiline mean steady-state half life is 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B. - Absorption - Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 1 hour. The absolute bioavailability of rasagiline is about 36%. - Food does not affect the Tmax of rasagiline, although Cmax and exposure (AUC) are decreased by approximately 60% and 20%, respectively, when the drug is taken with a high fat meal. Because AUC is not significantly affected, AZILECT can be administered with or without food. - Distribution - The mean volume of distribution at steady-state is 87 L, indicating that the tissue binding of rasagiline is in excess of plasma protein binding. Plasma protein binding ranges from 88-94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1-100 ng/mL. - Metabolism and Elimination - Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylation to yield 1-aminoindan (AI), 3-hydroxy-N-propargyl-1 aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP1A2 being the major isoenzyme involved in rasagiline metabolism. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. - After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine. - Special Populations - Hepatic Impairment - Following repeat dose administration (7 days) of rasagiline (1 mg/day) in subjects with mild hepatic impairment (Child-Pugh score 5-6), AUC and Cmax were increased by 2 fold and 1.4 fold, respectively, compared to healthy subjects. In subjects with moderate hepatic impairment (Child-Pugh score 7-9), AUC and Cmax were increased by 7 fold and 2 fold, respectively, compared to healthy subjects . - Renal Impairment - Following repeat dose administration (8 days) of rasagiline (1 mg/day) in subjects with moderate renal impairment, rasagiline exposure (AUC) was similar to rasagiline exposure in healthy subjects, while the major metabolite 1-AI exposure (AUC) was increased 1.5- fold in subjects with moderate renal impairment, compared to healthy subjects. Because 1-AI is not an MAO inhibitor, no dose adjustment is needed for patients with mild and moderate renal impairment. Data are not available for patients with severe renal impairment. - Elderly - Since age has little influence on rasagiline pharmacokinetics, it can be administered at the recommended dose in the elderly (> 65 years). - Pediatric - AZILECT has not been investigated in patients below 18 years of age. - Gender - The pharmacokinetic profile of rasagiline is similar in men and women. - Drug-Drug Interactions - Levodopa - A study in Parkinson’s disease patients, in which the effect of levodopa/carbidopa (LD/CD) on rasagiline pharmacokinetics at steady state was investigated, showed that the pharmacokinetics of rasagiline were not affected by concomitant administration of LD/CD. - Effect of Other Drugs on the Metabolism of AZILECT - In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of rasagiline. There is the potential for inhibitors of this enzyme to alter AZILECT clearance when coadministered . - Ciprofloxacin: When ciprofloxacin, an inhibitor of CYP1A2, was administered to healthy volunteers (n=12) at 500 mg (BID) with rasagiline at 2 mg/day, the AUC of rasagiline increased by 83% and there was no change in the elimination half life . - Theophylline: Coadministration of rasagiline 1 mg/day and theophylline, a substrate of CYP1A2, up to 500 mg twice daily to healthy subjects (n=24) did not affect the pharmacokinetics of either drug. - Antidepressants: Severe CNS toxicity (occasionally fatal) associated with hyperpyrexia as part of a serotonin syndrome, has been reported with combined treatment of an antidepressant (e.g., from one of many classes including tricyclic or tetracyclic antidepressants, SSRIs, SNRIs, triazolopyridine antidepressants) and nonselective MAOI or a selective MAO-B inhibitor . - Effect of AZILECT on Other Drugs - No additional in vivo trials have investigated the effect of AZILECT on other drugs metabolized by the cytochrome P450 enzyme system. In vitro studies showed that rasagiline at a concentration of 1 mcg/ml (equivalent to a level that is 160 times the average Cmax ~ 5.9-8.5 ng/mL in Parkinson’s disease patients after 1 mg rasagiline multiple dosing) did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results indicate that rasagiline is unlikely to cause any clinically significant interference with substrates of these enzymes. ## Nonclinical Toxicology - Carcinogenesis - Two-year carcinogenicity studies were conducted in mice at oral doses of 1, 15, and 45 mg/kg/day and in rats at oral doses of 0.3, 1, and 3 mg/kg/day (males) or 0.5, 2, 5, and 17 mg/kg/day (females). In rats, there was no increase in tumors at any dose tested. Plasma exposures (AUC) at the highest dose tested were approximately 33 and 260 times, in male and female rats, respectively, that in humans at the maximum recommended human dose (MRHD) of 1 mg/day. - In mice, there was an increase in lung tumors (combined adenomas/carcinomas) at 15 and 45 mg/kg in males and females. At the lowest dose tested, plasma AUCs were approximately 5 times those expected in humans at the MRHD. - The carcinogenic potential of rasagiline administered in combination with levodopa/carbidopa has not been examined. - Mutagenesis - Rasagiline was reproducibly clastogenic in in vitro chromosomal aberration assays in human lymphocytes in the presence of metabolic activation and was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the absence and presence of metabolic activation. Rasagiline was negative in the in vitro bacterial reverse mutation (Ames) assay and in the in vivo micronucleus assay in mice. Rasagiline was also negative in the in vivo micronucleus assay in mice when administered in combination with levodopa/carbidopa. - Impairment of Fertility - Rasagiline had no effect on mating performance or fertility in rats treated prior to and throughout the mating period and continuing in females through gestation day 17 at oral doses of up to 3 mg/kg/day (approximately 30 times the plasma AUC in humans at the MRHD). The effect of rasagiline administered in combination with levodopa/carbidopa on mating and fertility has not been examined. # Clinical Studies - The effectiveness of AZILECT for the treatment of Parkinson’s disease was established in four 18- to 26-week, randomized, placebo-controlled trials, as initial monotherapy or adjunct therapy. - Study 1 was a double-blind, randomized, fixed-dose parallel group, 26-week study in early Parkinson’s disease patients not receiving any concomitant dopaminergic therapy at the start of the study. The majority of the patients were not treated with medications for Parkinson’s disease before receiving AZILECT. - In Study 1, 404 patients were randomly assigned to receive placebo (138 patients), AZILECT 1 mg/day (134 patients) or AZILECT 2 mg/day (132 patients). Patients were not allowed to take levodopa, dopamine agonists, selegiline or amantadine, but could take stable doses of anticholinergic medication, if necessary. The average Parkinson’s disease duration was approximately 1 year (range 0 to 11 years). - The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS), . The UPDRS is a multi-item rating scale that measures the ability of a patient to perform mental and motor tasks as well as activities of daily living. A reduction in the score represents improvement and a beneficial change from baseline appears as a negative number. - AZILECT (1 or 2 mg once daily) was superior to placebo on the primary measure of effectiveness in patients receiving six months of treatment and not on dopaminergic therapy. The effectiveness of AZILECT 1 mg and 2 mg was comparable. Table 4 shows the results of Study 1. There were no differences in effectiveness based on age or gender between AZILECT 1 mg/day and placebo. - Study 2 was a double-blind, randomized, placebo-controlled, parallel group, 18-week study, investigating AZILECT 1 mg as adjunct therapy to dopamine agonists without levodopa. Patients were on a stable dose of dopamine agonist (ropinirole, mean 8 mg/day or pramipexole, mean 1.5 mg/day) therapy for ≥ 30 days, but at doses not sufficient to control Parkinson’s disease symptoms. - In Study 2, 321 patients randomly received placebo (162 patients) or AZILECT 1 mg/day (159 patients) and had a post-baseline assessment. The average Parkinson’s disease duration was approximately 2 years (range 0.1 to 14.5 years). - The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS) . - In Study 2, AZILECT 1 mg was superior to placebo on the primary measure of effectiveness (see Table 5). - Secondary outcome assessment of the individual subscales of the UPDRS indicates that the UPDRS Part III motor subscale was primarily responsible for the overall AZILECT effect on the UPDRS score (see Table 6). - Study 3 and Study 4 were randomized, multinational trials conducted in more advanced Parkinson’s disease patients treated chronically with levodopa and experiencing motor fluctuations (including but not limited to, end of dose “wearing off,” sudden or random “off,” etc.). Study 3 was conducted in North America (U.S. and Canada) and compared AZILECT 0.5 mg and 1 mg daily to placebo. Study 4 was conducted outside of North America in Europe, Argentina and Israel, and compared AZILECT 1 mg daily to placebo. - Patients had Parkinson’s disease for an average of 9 years (range 5 months to 33 years), had taken levodopa for an average of 8 years (range 5 months to 32 years), and had motor fluctuations for approximately 3 to 4 years (range 1 month to 23 years). Patients kept home Parkinson’s disease diaries just prior to baseline and at specified intervals during the trial. Diaries recorded one of the following four conditions for each half-hour interval over a 24-hour period: “ON” (period of relatively good function and mobility) as either “ON” with no dyskinesia or without troublesome dyskinesia, or “ON” with troublesome dyskinesia, “OFF” (period of relatively poor function and mobility) or asleep. “Troublesome” dyskinesia is defined as dyskinesia that interferes with the patient’s daily activity. All patients had inadequate control of their motor symptoms with motor fluctuations typical of advanced stage disease despite receiving levodopa/decarboxylase inhibitor. The average dose of levodopa taken with a decarboxylase inhibitor was approximately 700 to 800 mg (range 150 to 3000 mg/day). Patients continued their stable doses of additional anti-PD medications at entry into the trials. Approximately 65% of patients in both studies were also taking a dopamine agonist. In the North American study (Study 3), approximately 35% of patients took entacapone with levodopa/decarboxylase inhibitor. The majority of patients taking entacapone were also taking a dopamine agonist. - In Study 3 and Study 4, the primary measure of effectiveness was the change in the mean number of hours spent in the “OFF” state at baseline compared to the mean number of hours spent in the “OFF” state during the treatment period. - In Study 3, patients were randomly assigned to receive placebo (159 patients), AZILECT 0.5 mg/day (164 patients), or AZILECT 1 mg/day (149 patients) for 26 weeks. Patients averaged 6 hours daily in the “OFF” state at baseline as confirmed by home diaries. - In Study 4, patients were randomly assigned to receive placebo (229 patients), AZILECT 1 mg/day (231 patients) or a COMT inhibitor (active comparator), taken along with scheduled doses of levodopa/decarboxylase inhibitor (227 patients) for 18 weeks. Patients averaged 5.6 hours daily in the “OFF” state at baseline as confirmed by home diaries. - In Study 3 and Study 4, AZILECT 1 mg once daily reduced “OFF” time compared to placebo when added to levodopa in patients experiencing motor fluctuations (Tables 7 and 8). The lower dose (0.5 mg) of AZILECT also significantly reduced “OFF” time (Table 7), but had a numerically smaller effect than the 1 mg dose of AZILECT. In Study 4, the active comparator also reduced “OFF” time when compared to placebo. - In Study 3 and Study 4, dose reduction of levodopa was allowed within the first 6 weeks, if dopaminergic side effects developed including dyskinesia or hallucinations. In Study 3, the levodopa dose was reduced in 8% of patients in the placebo group and in 16% and 17% of patients in the 0.5 mg/day and 1 mg/day AZILECT groups, respectively. When levodopa was reduced, the dose was reduced by 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In Study 4, levodopa dose reduction occurred in 6% of patients in the placebo group and in 9% in the AZILECT 1 mg/day groups, respectively. When levodopa was reduced, it was reduced by 13% and 11% in the placebo and the AZILECT groups, respectively. - There were no differences in effectiveness based on age or gender between AZILECT 1 mg/day and placebo. - Several secondary outcome assessments in the two studies showed statistically significant improvements with rasagiline. These included effects on the activities of daily living (ADL) subscale of the UPDRS performed during an “OFF” period and the motor subscale of the UPDRS performed during an “ON” period. In both scales, a negative response represents improvement. Tables 9 and 10 show these results for Studies 3 and 4. # How Supplied - AZILECT 0.5 mg Tablets: - White to off-white, round, flat, beveled tablets, debossed with “GIL 0.5” on one side and plain on the other side. Supplied as bottles of 30 tablets (NDC 68546-142-56). - AZILECT 1 mg Tablets: - White to off-white, round, flat, beveled tablets, debossed with “GIL 1” on one side and plain on the other side. Supplied as bottles of 30 tablets (NDC 68546-229-56). - Storage: - Store at 25°C (77°F) with excursions permitted to 15°-30°C (59°-86°F). ## Storage There is limited information regarding Rasagiline Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hypertension - Advise patients that treatment with recommended doses of AZILECT may be associated with elevations of blood pressure. Tell patients who experience elevation of blood pressure while taking AZILECT to contact their healthcare provider. - The risk of using higher than recommended daily doses of AZILECT should be explained, and a brief description of the tyramine associated hypertensive reaction provided. - Advise patients to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of AZILECT because of the potential for large increases in blood pressure. If patients eat foods very rich in tyramine and do not feel well soon after eating, they should contact their healthcare provider . - Serotonin Syndrome - Tell patients to inform their physician if they are taking, or planning to take, any prescription or over-the-counter drugs, especially antidepressants and over-the-counter cold medications, since there is a potential for interaction with AZILECT. Because patients should not use meperidine or certain other analgesics with AZILECT, they should contact their healthcare provider before taking analgesics . - Falling Asleep During Activities of Daily Living and Somnolence - Advise and alert patients about the potential for sedating effects associated with AZILECT and other dopaminergic medications, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with AZILECT and other dopaminergic medications to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of AZILECT. - Because of possible additive effects, advise patients to exercise caution when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants) in combination with AZILECT or when taking concomitant medications that increase plasma levels of rasagiline (e.g., ciprofloxacin) . - Ciprofloxacin or Other CYP1A2 Inhibitors - Inform patients that they should contact their healthcare provider of AZILECT if they take ciprofloxacin or a similar drug that could increase blood levels of rasagiline because of the need to adjust the dose of AZILECT . - Hepatic Impairment - Tell patients who have hepatic problems to contact their healthcare provider regarding possible changes in AZILECT dosing . - Hypotension / Orthostatic Hypotension - Patients should be advised that they may develop orthostatic hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment). Accordingly, patients should be cautioned against standing up rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially, at the initiation of treatment with AZILECT . - Dyskinesia - Advise patients taking AZILECT as adjunct to levodopa that there is a possibility of dyskinesia or increased dyskinesia . - Hallucinations / Psychotic-Like Behavior - Inform patients that hallucinations or other manifestations of psychotic-like behavior can occur when taking AZILECT. Advise patients that, if they have a major psychotic disorder, that AZILECT should not ordinarily be used because of the risk of exacerbating the psychosis. Patients with a major psychotic disorder should also be aware that many treatments for psychosis may decrease the effectiveness of AZILECT . - Impulse Control/Compulsive Behaviors - Advise patients that they may experience intense urges to gamble, increased sexual urges, other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease (including AZILECT). Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges, or other urges while being treated with AZILECT. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges, or other intense urges while taking AZILECT. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking AZILECT . - Withdrawal-Emergent Hyperpyrexia and Confusion - Tell patients to contact their healthcare provider if they wish to discontinue AZILECT . - Missing Dose - Instruct patients to take AZILECT as prescribed. If a dose is missed, the patient should not double-up the dose of AZILECT. The next dose should be taken at the usual time on the following day. # Precautions with Alcohol - Alcohol-Rasagiline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - AZILECT® # Look-Alike Drug Names - Azilect® — Aricept® # Drug Shortage Status # Price	Rasagiline Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Rasagiline is a monoamine oxidase (MAO)-B inhibitor (MAOI) that is FDA approved for the {{{indicationType}}} of parkinson’s disease. Common adverse reactions include flu syndrome, arthralgia, depression, and dyspepsia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - When AZILECT is prescribed as monotherapy or as adjunct therapy in patients not taking levodopa, patients may start AZILECT at the recommended dose of 1 mg administered orally once daily. - In patients taking levodopa, with or without other PD drugs (e.g., dopamine agonist, amantadine, anticholinergics), the recommended initial dose of AZILECT is 0.5 mg once daily. If the patient tolerates the daily 0.5 mg dose, but a sufficient clinical response is not achieved, the dose may be increased to 1 mg once daily. When AZILECT is used in combination with levodopa, a reduction of the levodopa dose may be considered, based upon individual response. - The recommended doses of AZILECT should not be exceeded because of risk of hypertension. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rasagiline in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasagiline in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Rasagiline in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rasagiline in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasagiline in pediatric patients. # Contraindications - AZILECT is contraindicated for use with meperidine, tramadol, methadone, propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors, because of risk of serotonin syndrome. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with these medications. - AZILECT is contraindicated for use with St. John’s wort and with cyclobenzaprine. - AZILECT is contraindicated for use with dextromethorphan because of risk of episode of psychosis or bizarre behavior. # Warnings ### Precautions - Hypertension - Exacerbation of hypertension may occur during treatment with AZILECT. Medication adjustment may be necessary if elevation of blood pressure is sustained. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting AZILECT. - In Study 3, AZILECT (1 mg/day) given in conjunction with levodopa, produced an increased incidence of significant blood pressure elevation (systolic > 180 or diastolic > 100 mm Hg) of 4% compared to 3% for placebo [see Adverse Reactions (6.1)]. - When used as an adjunct to levodopa (Studies 3 and 4), the risk for developing post-treatment high blood pressure (e.g., systolic > 180 or diastolic >100 mm Hg) combined with a significant increase from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for AZILECT (2%) compared to placebo (1%). - Dietary tyramine restriction is not required during treatment with recommended doses of AZILECT. However, certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine that could potentially cause severe hypertension because of tyramine interaction (including various clinical syndromes referred to as hypertensive urgency, crisis, or emergency) in patients taking AZILECT, even at the recommended doses, due to increased sensitivity to tyramine. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of AZILECT because of the potential for large increases in blood pressure including clinical syndromes referred to as hypertensive urgency, crisis, or emergency. AZILECT is a selective inhibitor of MAO-B at the recommended doses of 0.5 or 1 mg daily. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses. - Serotonin Syndrome - Serotonin syndrome has been reported with concomitant use of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a nonselective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (AZILECT). Serotonin syndrome has also been reported with concomitant use of AZILECT with meperidine, tramadol, methadone, or propoxyphene. AZILECT is contraindicated for use with meperidine, tramadol, methadone, propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors. - In the postmarketing period, potentially life-threatening serotonin syndrome has been reported in patients treated with antidepressants concomitantly with AZILECT. Concomitant use of AZILECT with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommende. - The symptoms of serotonin syndrome have included behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor). Serotonin syndrome can result in death. - AZILECT clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with AZILECT, and the potential drug interaction between AZILECT and antidepressants has not been studied systematically. Although a small number of AZILECT-treated patients were concomitantly exposed to antidepressants (tricyclics n=115; SSRIs n=141), the exposure, both in dose and number of subjects, was not adequate to rule out the possibility of an untoward reaction from combining these agents. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. Because of the long half-lives of certain antidepressants (e.g., fluoxetine and its active metabolite), at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of AZILECT. - Falling Asleep During Activities of Daily Living and Somnolence - It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should monitor patients for drowsiness or sleepiness, because some of the events occur well after initiation of treatment with dopaminergic medication. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. - Cases of patients treated with AZILECT and other dopaminergic medications have reported falling asleep while engaged in activities of daily living including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on AZILECT with other dopaminergic medications, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1-year after initiation of treatment. - In Study 3, somnolence was a common occurrence in patients receiving AZILECT and was more frequent in patients with Parkinson’s disease receiving AZILECT than in respective patients receiving placebo (6% AZILECT compared to 4% Placebo). - Before initiating treatment with AZILECT, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with AZILECT such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase rasagiline plasma levels (e.g., ciprofloxacin). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), AZILECT should ordinarily be discontinued. If a decision is made to continue these patients on AZILECT, advise them to avoid driving and other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. - Ciprofloxacin or Other CYP1A2 Inhibitors - Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily. - Hepatic Impairment - Rasagiline plasma concentration may increase in patients with hepatic impairment. Patients with mild hepatic impairment should be given the dose of AZILECT 0.5 mg once daily. AZILECT should not be used in patients with moderate or severe hepatic impairment. - Hypotension / Orthostatic Hypotension - In Study 3, the incidence of orthostatic hypotension consisting of a systolic blood pressure decrease (≥ 30 mm Hg) or a diastolic blood pressure decrease (> 20 mm Hg) after standing was 13% with AZILECT (1 mg/day) compared to 9% with placebo. - At the 1 mg dose, the frequency of orthostatic hypotension (at any time during the study) was approximately 44% for AZILECT vs 33% for placebo for mild to moderate systolic blood pressure decrements (> 20 mm Hg), 40% for AZILECT vs 33% for placebo for mild to moderate diastolic blood pressure decrements (> 10 mm Hg), 7% for AZILECT vs 3% for placebo for severe systolic blood pressure decrements (> 40 mm Hg), and 9% for AZILECT vs 6% for placebo for severe diastolic blood pressure decrements (≥ 20 mm Hg). There was also an increased risk for some of these abnormalities at the lower 0.5 mg daily dose and for an individual patient having mild to moderate or severe orthostatic hypotension for both systolic and diastolic blood pressure. - In Study 2 where AZILECT was given as an adjunct therapy in patients not taking concomitant levodopa, there were 5 reports of orthostatic hypotension in patients taking AZILECT 1 mg (3.1%) and 1 report in patients taking placebo (0.6%). - Clinical trial data further suggest that orthostatic hypotension occurs most frequently in the first two months of AZILECT treatment and tends to decrease over time. - Some patients treated with AZILECT experienced a mildly increased risk for significant decreases in blood pressure unrelated to standing but while supine. - The risk for post-treatment hypotension (e.g., systolic < 90 or diastolic < 50 mm Hg) combined with a significant decrease from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for AZILECT 1 mg (3.2%) compared to placebo (1.3%). - There was no clear increased risk for lowering of blood pressure or postural hypotension associated with AZILECT 1 mg/day as monotherapy. - When used as an adjunct to levodopa, postural hypotension was also reported as an adverse reaction in approximately 6% of patients treated with AZILECT 0.5 mg, 9% of patients treated with AZILECT 1 mg and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with AZILECT 1 mg/day, no patients treated with AZILECT 0.5 mg/day and no placebo-treated patients. - Dyskinesia - When used as an adjunct to levodopa, AZILECT may cause dyskinesia or potentiate dopaminergic side effects and exacerbate pre-existing dyskinesia. In Study 3, the incidence of dyskinesia was 18% for patients treated with 0.5 mg or 1 mg AZILECT as an adjunct to levodopa and 10% for patients treated with placebo as an adjunct to levodopa. Decreasing the dose of levodopa may mitigate this side effect. - Hallucinations / Psychotic-Like Behavior - In the monotherapy study (Study 1), the incidence of hallucinations reported as an adverse event was 1.3% in patients treated with AZILECT 1 mg and 0.7% in patients treated with placebo. In Study 1, the incidence of hallucinations reported as an adverse reaction and leading to drug discontinuation and premature withdrawal was 1.3% in patients treated with AZILECT 1 mg and 0% in placebo-treated patients. - When studied as an adjunct therapy without levodopa (Study 2), hallucinations were reported as an adverse reaction in 1.2% of patients treated with 1 mg/day AZILECT and 1.8% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from the clinical trial in 0.6% of patients treated with AZILECT 1 mg/day and in none of the placebo-treated patients. - When studied as an adjunct to levodopa (Study 3), the incidence of hallucinations was approximately 5% in patients treated with AZILECT 0.5 mg/day, 4% in patients treated with AZILECT 1 mg/day, and 3% in patients treated with placebo. The incidence of hallucinations leading to drug discontinuation and premature withdrawal was about 1% in patients treated with 0.5 mg AZILECT and 1 mg AZILECT/day, and 0% in placebo-treated patients. - Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with AZILECT or after starting or increasing the dose of AZILECT. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. - Patients should be informed of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop. - Patients with a major psychotic disorder should ordinarily not be treated with AZILECT because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, many treatments for psychosis that decrease central dopaminergic tone may decrease the effectiveness of AZILECT. - Consider dose reduction or stopping the medication if a patient develops hallucinations or psychotic like behaviors while taking AZILECT. - Impulse Control / Compulsive Behaviors - Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including AZILECT, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with AZILECT. Consider dose reduction or stopping the medication if a patient develops such urges while taking AZILECT. - Withdrawal-Emergent Hyperpyrexia and Confusion - A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. - Melanoma - Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. - For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the rates of adverse reactions observed in practice. - During the clinical development of AZILECT, Parkinson’s disease patients received AZILECT as initial monotherapy (Study 1) and as adjunct therapy (Study 2, Study 3, Study 4). As the populations in these studies differ, not only in the adjunct use of dopamine agonists or levodopa during AZILECT treatment, but also in the severity and duration of their disease, the adverse reactions are presented separately for each study. - Monotherapy Use of AZILECT - In Study 1, approximately 5% of the 149 patients treated with AZILECT discontinued treatment due to adverse reactions compared to 2% of the 151 patients who received placebo. - The only adverse reaction that led to the discontinuation of more than one patient was hallucinations. - The most commonly observed adverse reactions in Study 1 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists adverse reactions that occurred in 2% or greater of patients receiving AZILECT as monotherapy and were numerically more frequent than in the placebo group in Study 1. - Adjunct Use of AZILECT - AZILECT was studied as an adjunct therapy without levodopa (Study 2), or as an adjunct therapy to levodopa, with some patients also taking dopamine agonists, COMT inhibitors, anticholinergics, or amantadine (Study 3 and Study 4). - In Study 2, approximately 8% of the 162 patients treated with AZILECT discontinued treatment due to adverse reactions compared to 4% of the 164 patients who received placebo. - Adverse reactions that led to the discontinuation of more than one patient were nausea and dizziness. - The most commonly observed adverse reactions in Study 2 (incidence in AZILECT-treated patients 3% or greater than incidence in placebo-treated patients) included peripheral edema, fall, arthralgia, cough, and insomnia. Table 2 lists adverse reactions that occurred in 2% or greater in patients receiving AZILECT as adjunct therapy without levodopa and numerically more frequent than in the placebo group in Study 2. - In Study 3, adverse event reporting was considered more reliable than Study 4; therefore, only the adverse event data from Study 3 are presented below. - In Study 3, approximately 9% of the 164 patients treated with AZILECT 0.5 mg/day and 7% of the 149 patients treated with AZILECT 1 mg/day discontinued treatment due to adverse reactions, compared to 6% of the 159 patients who received placebo. The adverse reactions that led to discontinuation of more than one AZILECT-treated patient were diarrhea, weight loss, hallucination, and rash. - The most commonly observed adverse reactions in Study 3 (incidence in AZILECT-treated patients 3% or greater than the incidence in placebo-treated patients) included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, fall and tenosynovitis. - Table 3 lists adverse reactions that occurred in 2% or greater of patients treated with AZILECT 1 mg/day and that were numerically more frequent than the placebo group in Study 3. - Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth. - There were no significant differences in the safety profile based on age or gender. - During all Parkinson’s disease phase 2/3 clinical trials, the long-term safety profile was similar to that observed with shorter duration exposure. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Rasagiline in the drug label. # Drug Interactions - Meperidine - Serious, sometimes fatal reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors. - Dextromethorphan - The concomitant use of AZILECT and dextromethorphan was not allowed in clinical studies. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of AZILECT’s MAO inhibitory activity, dextromethorphan is contraindicated for use with AZILECT. - MAO Inhibitors - AZILECT is contraindicated for use with other MAO inhibitors because of the increased risk of nonselective MAO inhibition that may lead to a hypertensive crisis. - Sympathomimetic Medications - The concomitant use of AZILECT and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAO inhibitors. Hypertensive crisis has been reported in patients taking the recommended dose of AZILECT and sympathomimetic medications. Severe hypertension has been reported in patients taking the recommended dose of AZILECT and ophthalmic drops containing sympathomimetic medications. - Because AZILECT is a selective MAOI, hypertensive reactions are not ordinarily expected with the concomitant use of sympathomimetic medications. Nevertheless, caution should be exercised when concomitantly using recommended doses of AZILECT with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies. - Antidepressants - Concomitant use of AZILECT with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended. Concomitant use of AZILECT and MAO inhibitors is contraindicated. - Ciprofloxacin or Other CYP1A2 Inhibitors - Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. This could result in increased adverse events. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily. - Tyramine/Rasagiline Interaction - MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a tyramine reaction with hypertension including clinical syndromes referred to as hypertensive urgency, crisis, or emergency. Foods and medications containing large amounts of exogenous amines (e.g., from fermented cheese, herring, over-the-counter cough/cold medications) may cause release of norepinephrine resulting in a rise in systemic blood pressure. - Results of a special tyramine challenge study indicate that rasagiline is selective for MAO-B at recommended doses and can be used without dietary tyramine restriction. However, certain foods may contain very high amounts (i.e., 150 mg or greater) of tyramine and could potentially cause a hypertensive reaction in individual patients taking AZILECT due to increased sensitivity to tyramine. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses. - There were no cases of hypertensive crisis in the clinical development program associated with 1 mg daily AZILECT treatment, in which most patients did not follow dietary tyramine restriction. - There have been postmarketing reports of patients who experienced significantly elevated blood pressure (including rare cases of hypertensive crisis) after ingestion of unknown amounts of tyramine-rich foods while taking recommended doses of AZILECT. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of AZILECT. - Dopaminergic Antagonists - It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of AZILECT. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies of rasagiline in pregnant women. AZILECT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - In a combined mating/fertility and embryo-fetal development study in pregnant rats, no effect on embryo-fetal development was observed at oral doses up to 3 mg/kg/day (approximately 30 times the plasma exposure (AUC) in humans at the maximum recommended human dose [MRHD, 1 mg/day]). - In pregnant rabbits administered rasagiline throughout the period of organogenesis at oral doses of up to 36 mg/kg/day, no developmental toxicity was observed. At the highest dose tested, the plasma AUC was approximately 800 times that in humans at the MRHD. - In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) orally during gestation and lactation, offspring survival was decreased and offspring body weight was reduced at 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the plasma AUC in humans at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is similar to the MRHD on a mg/m2 basis. The effect of rasagiline on physical and behavioral development was not adequately assessed in this study. - Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) orally throughout the period of organogenesis, there was an increased incidence of wavy ribs in fetuses from rats treated with rasagiline in combination with levodopa/carbidopa at 1/80/20 mg/kg/day (approximately 8 times the rasagiline plasma AUC in humans at the MRHD and similar to the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m2 basis). In pregnant rabbits dosed orally throughout the period of organogenesis with rasagiline alone (3 mg/kg) or in combination with levodopa/carbidopa (rasagiline: 0.1, 0.6, 1.2 mg/kg, levodopa/carbidopa: 80/20 mg/kg/day), an increase in embryo-fetal death was noted at rasagiline doses of 0.6 and 1.2 mg/kg/day when administered in combination with levodopa/carbidopa (approximately 7 and 13 times, respectively, the rasagiline plasma AUC in humans at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (similar to the MRHD on a mg/m2 basis) and to a greater extent when rasagiline (at all doses; 1-13 times the rasagiline plasma AUC in humans at the MRHD) was administered in combination with levodopa/carbidopa. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rasagiline in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Rasagiline during labor and delivery. ### Nursing Mothers - In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in humans. - It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AZILECT is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Approximately half of patients in clinical trials were 65 years and over. There were no significant differences in the safety profile of the geriatric and nongeriatric patients. ### Gender There is no FDA guidance on the use of Rasagiline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Rasagiline with respect to specific racial populations. ### Renal Impairment - Dose adjustment of AZILECT is not required for patients with mild or moderate renal impairment because AZILECT plasma concentrations are not increased in patients with moderate renal impairment. Rasagiline has not been studied in patients with severe renal impairment. ### Hepatic Impairment - Rasagiline plasma concentration may be increased in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should not exceed a dose of 0.5 mg/day. AZILECT should not be used in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Rasagiline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Rasagiline in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Rasagiline in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Rasagiline in the drug label. # Overdosage ## Acute Overdose - In a dose escalation study in patients on chronic levodopa therapy treated with 10 mg of AZILECT there were three reports of cardiovascular side effects (including hypertension and postural hypotension) which resolved following treatment discontinuation. - Although no cases of overdose have been observed with AZILECT during the clinical development program, the following description of presenting symptoms and clinical course is based upon overdose descriptions of nonselective MAO inhibitors. - The signs and symptoms of nonselective MAOI overdose may not appear immediately. Delays of up to 12 hours after ingestion of drug and the appearance of signs may occur. The peak intensity of the syndrome may not be reached until for a day following the overdose. Death has been reported following overdose; therefore, immediate hospitalization, with continuous patient observation and monitoring for at least two days following the ingestion of such drugs in overdose, is strongly recommended. - The severity of the clinical signs and symptoms of MAOI overdose varies and may be related to the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved. - Signs and symptoms of MAOI overdose may include: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. - There is no specific antidote for AZILECT overdose. The following suggestions are offered based upon the assumption that AZILECT overdose may be modeled after nonselective MAO inhibitor poisoning. Treatment of overdose with nonselective MAO inhibitors is symptomatic and supportive. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential. For this reason, in cases of overdose with AZILECT, dietary tyramine restriction should be observed for several weeks to reduce the risk of hypertensive tyramine reaction. - A poison control center should be called for the most current treatment guidelines. - A postmarketing report described a single patient who developed a nonfatal serotonin syndrome after ingesting 100 mg of AZILECT in a suicide attempt. Another patient who was treated in error with 4 mg AZILECT daily and tramadol also developed a serotonin syndrome. One patient who was treated in error with 3 mg AZILECT daily experienced alternating episodes of vascular fluctuations consisting of hypertension and orthostatic hypotension. ## Chronic Overdose There is limited information regarding Chronic Overdose of Rasagiline in the drug label. # Pharmacology ## Mechanism of Action - AZILECT is a selective, irreversible MAO-B inhibitor indicated for the treatment of idiopathic Parkinson’s disease. The results of a clinical trial designed to examine the effects of AZILECT on blood pressure when it is administered with increasing doses of tyramine indicates the functional selectivity can be incomplete when healthy subjects ingest large amounts of tyramine while receiving recommended doses of AZILECT. The selectivity for inhibiting MAO-B diminishes in a dose-related manner. - MAO, a flavin-containing enzyme, is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. MAO-B is the major form in the human brain. In ex vivo animal studies in brain, liver, and intestinal tissues, rasagiline was shown to be a potent, irreversible monoamine oxidase type B (MAO-B) selective inhibitor. Rasagiline at the recommended therapeutic dose was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The precise mechanisms of action of rasagiline are unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline’s beneficial effects seen in models of dopaminergic motor dysfunction. ## Structure - AZILECT® tablets contain rasagiline (as the mesylate), a propargylamine-based drug indicated for the treatment of idiopathic Parkinson’s disease. It is designated chemically as: 1H-Inden-1-amine, 2, 3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate. The empirical formula of rasagiline mesylate is (C12H13N)CH4SO3 and its molecular weight is 267.34. - Its structural formula is: - Rasagiline mesylate is a white to off-white powder, freely soluble in water or ethanol and sparingly soluble in isopropanol. Each AZILECT tablet for oral administration contains rasagiline mesylate equivalent to 0.5 mg or 1 mg of rasagiline base. - Each AZILECT tablet also contains the following inactive ingredients: mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid and talc. ## Pharmacodynamics - Tyramine Challenge Test - Results of a tyramine challenge study indicate that rasagiline at recommended doses is relatively selective for inhibiting MAO-B and can be used without dietary tyramine restriction. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts of tyramine (i.e., 150 mg or greater) and could potentially cause severe hypertension caused by tyramine interaction in patients taking AZILECT due to mild increased sensitivity to tyramine at recommended doses. Relative selectivity of AZILECT for inhibiting MAO-B diminished in a dose-related manner as the dose progressively increased above the highest recommended daily dose (1 mg). - Platelet MAO Activity in Clinical Studies - Studies in healthy subjects and in Parkinson’s disease patients have shown that rasagiline inhibits platelet MAO-B irreversibly. The inhibition lasts at least 1 week after last dose. Almost 25-35% MAO-B inhibition was achieved after a single rasagiline dose of 1 mg/day and more than 55% of MAO-B inhibition was achieved after a single rasagiline dose of 2 mg/day. Over 90% inhibition was achieved 3 days after rasagiline daily dosing at 2 mg/day and this inhibition level was maintained 3 days postdose. Multiple doses of rasagiline of 0.5, 1 and 2 mg per day resulted in complete MAO-B inhibition. ## Pharmacokinetics - Rasagiline in the range of 1-6 mg demonstrated a more than proportional increase in AUC, while Cmax was dose proportional. Rasagiline mean steady-state half life is 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B. - Absorption - Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 1 hour. The absolute bioavailability of rasagiline is about 36%. - Food does not affect the Tmax of rasagiline, although Cmax and exposure (AUC) are decreased by approximately 60% and 20%, respectively, when the drug is taken with a high fat meal. Because AUC is not significantly affected, AZILECT can be administered with or without food. - Distribution - The mean volume of distribution at steady-state is 87 L, indicating that the tissue binding of rasagiline is in excess of plasma protein binding. Plasma protein binding ranges from 88-94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1-100 ng/mL. - Metabolism and Elimination - Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylation to yield 1-aminoindan (AI), 3-hydroxy-N-propargyl-1 aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP1A2 being the major isoenzyme involved in rasagiline metabolism. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. - After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine. - Special Populations - Hepatic Impairment - Following repeat dose administration (7 days) of rasagiline (1 mg/day) in subjects with mild hepatic impairment (Child-Pugh score 5-6), AUC and Cmax were increased by 2 fold and 1.4 fold, respectively, compared to healthy subjects. In subjects with moderate hepatic impairment (Child-Pugh score 7-9), AUC and Cmax were increased by 7 fold and 2 fold, respectively, compared to healthy subjects [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. - Renal Impairment - Following repeat dose administration (8 days) of rasagiline (1 mg/day) in subjects with moderate renal impairment, rasagiline exposure (AUC) was similar to rasagiline exposure in healthy subjects, while the major metabolite 1-AI exposure (AUC) was increased 1.5- fold in subjects with moderate renal impairment, compared to healthy subjects. Because 1-AI is not an MAO inhibitor, no dose adjustment is needed for patients with mild and moderate renal impairment. Data are not available for patients with severe renal impairment. - Elderly - Since age has little influence on rasagiline pharmacokinetics, it can be administered at the recommended dose in the elderly (> 65 years). - Pediatric - AZILECT has not been investigated in patients below 18 years of age. - Gender - The pharmacokinetic profile of rasagiline is similar in men and women. - Drug-Drug Interactions - Levodopa - A study in Parkinson’s disease patients, in which the effect of levodopa/carbidopa (LD/CD) on rasagiline pharmacokinetics at steady state was investigated, showed that the pharmacokinetics of rasagiline were not affected by concomitant administration of LD/CD. - Effect of Other Drugs on the Metabolism of AZILECT - In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of rasagiline. There is the potential for inhibitors of this enzyme to alter AZILECT clearance when coadministered [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. - Ciprofloxacin: When ciprofloxacin, an inhibitor of CYP1A2, was administered to healthy volunteers (n=12) at 500 mg (BID) with rasagiline at 2 mg/day, the AUC of rasagiline increased by 83% and there was no change in the elimination half life [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. - Theophylline: Coadministration of rasagiline 1 mg/day and theophylline, a substrate of CYP1A2, up to 500 mg twice daily to healthy subjects (n=24) did not affect the pharmacokinetics of either drug. - Antidepressants: Severe CNS toxicity (occasionally fatal) associated with hyperpyrexia as part of a serotonin syndrome, has been reported with combined treatment of an antidepressant (e.g., from one of many classes including tricyclic or tetracyclic antidepressants, SSRIs, SNRIs, triazolopyridine antidepressants) and nonselective MAOI or a selective MAO-B inhibitor [see Warnings and Precautions (5.2)]. - Effect of AZILECT on Other Drugs - No additional in vivo trials have investigated the effect of AZILECT on other drugs metabolized by the cytochrome P450 enzyme system. In vitro studies showed that rasagiline at a concentration of 1 mcg/ml (equivalent to a level that is 160 times the average Cmax ~ 5.9-8.5 ng/mL in Parkinson’s disease patients after 1 mg rasagiline multiple dosing) did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results indicate that rasagiline is unlikely to cause any clinically significant interference with substrates of these enzymes. ## Nonclinical Toxicology - Carcinogenesis - Two-year carcinogenicity studies were conducted in mice at oral doses of 1, 15, and 45 mg/kg/day and in rats at oral doses of 0.3, 1, and 3 mg/kg/day (males) or 0.5, 2, 5, and 17 mg/kg/day (females). In rats, there was no increase in tumors at any dose tested. Plasma exposures (AUC) at the highest dose tested were approximately 33 and 260 times, in male and female rats, respectively, that in humans at the maximum recommended human dose (MRHD) of 1 mg/day. - In mice, there was an increase in lung tumors (combined adenomas/carcinomas) at 15 and 45 mg/kg in males and females. At the lowest dose tested, plasma AUCs were approximately 5 times those expected in humans at the MRHD. - The carcinogenic potential of rasagiline administered in combination with levodopa/carbidopa has not been examined. - Mutagenesis - Rasagiline was reproducibly clastogenic in in vitro chromosomal aberration assays in human lymphocytes in the presence of metabolic activation and was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the absence and presence of metabolic activation. Rasagiline was negative in the in vitro bacterial reverse mutation (Ames) assay and in the in vivo micronucleus assay in mice. Rasagiline was also negative in the in vivo micronucleus assay in mice when administered in combination with levodopa/carbidopa. - Impairment of Fertility - Rasagiline had no effect on mating performance or fertility in rats treated prior to and throughout the mating period and continuing in females through gestation day 17 at oral doses of up to 3 mg/kg/day (approximately 30 times the plasma AUC in humans at the MRHD). The effect of rasagiline administered in combination with levodopa/carbidopa on mating and fertility has not been examined. # Clinical Studies - The effectiveness of AZILECT for the treatment of Parkinson’s disease was established in four 18- to 26-week, randomized, placebo-controlled trials, as initial monotherapy or adjunct therapy. - Study 1 was a double-blind, randomized, fixed-dose parallel group, 26-week study in early Parkinson’s disease patients not receiving any concomitant dopaminergic therapy at the start of the study. The majority of the patients were not treated with medications for Parkinson’s disease before receiving AZILECT. - In Study 1, 404 patients were randomly assigned to receive placebo (138 patients), AZILECT 1 mg/day (134 patients) or AZILECT 2 mg/day (132 patients). Patients were not allowed to take levodopa, dopamine agonists, selegiline or amantadine, but could take stable doses of anticholinergic medication, if necessary. The average Parkinson’s disease duration was approximately 1 year (range 0 to 11 years). - The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS), [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)]. The UPDRS is a multi-item rating scale that measures the ability of a patient to perform mental and motor tasks as well as activities of daily living. A reduction in the score represents improvement and a beneficial change from baseline appears as a negative number. - AZILECT (1 or 2 mg once daily) was superior to placebo on the primary measure of effectiveness in patients receiving six months of treatment and not on dopaminergic therapy. The effectiveness of AZILECT 1 mg and 2 mg was comparable. Table 4 shows the results of Study 1. There were no differences in effectiveness based on age or gender between AZILECT 1 mg/day and placebo. - Study 2 was a double-blind, randomized, placebo-controlled, parallel group, 18-week study, investigating AZILECT 1 mg as adjunct therapy to dopamine agonists without levodopa. Patients were on a stable dose of dopamine agonist (ropinirole, mean 8 mg/day or pramipexole, mean 1.5 mg/day) therapy for ≥ 30 days, but at doses not sufficient to control Parkinson’s disease symptoms. - In Study 2, 321 patients randomly received placebo (162 patients) or AZILECT 1 mg/day (159 patients) and had a post-baseline assessment. The average Parkinson’s disease duration was approximately 2 years (range 0.1 to 14.5 years). - The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS) [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)]. - In Study 2, AZILECT 1 mg was superior to placebo on the primary measure of effectiveness (see Table 5). - Secondary outcome assessment of the individual subscales of the UPDRS indicates that the UPDRS Part III motor subscale was primarily responsible for the overall AZILECT effect on the UPDRS score (see Table 6). - Study 3 and Study 4 were randomized, multinational trials conducted in more advanced Parkinson’s disease patients treated chronically with levodopa and experiencing motor fluctuations (including but not limited to, end of dose “wearing off,” sudden or random “off,” etc.). Study 3 was conducted in North America (U.S. and Canada) and compared AZILECT 0.5 mg and 1 mg daily to placebo. Study 4 was conducted outside of North America in Europe, Argentina and Israel, and compared AZILECT 1 mg daily to placebo. - Patients had Parkinson’s disease for an average of 9 years (range 5 months to 33 years), had taken levodopa for an average of 8 years (range 5 months to 32 years), and had motor fluctuations for approximately 3 to 4 years (range 1 month to 23 years). Patients kept home Parkinson’s disease diaries just prior to baseline and at specified intervals during the trial. Diaries recorded one of the following four conditions for each half-hour interval over a 24-hour period: “ON” (period of relatively good function and mobility) as either “ON” with no dyskinesia or without troublesome dyskinesia, or “ON” with troublesome dyskinesia, “OFF” (period of relatively poor function and mobility) or asleep. “Troublesome” dyskinesia is defined as dyskinesia that interferes with the patient’s daily activity. All patients had inadequate control of their motor symptoms with motor fluctuations typical of advanced stage disease despite receiving levodopa/decarboxylase inhibitor. The average dose of levodopa taken with a decarboxylase inhibitor was approximately 700 to 800 mg (range 150 to 3000 mg/day). Patients continued their stable doses of additional anti-PD medications at entry into the trials. Approximately 65% of patients in both studies were also taking a dopamine agonist. In the North American study (Study 3), approximately 35% of patients took entacapone with levodopa/decarboxylase inhibitor. The majority of patients taking entacapone were also taking a dopamine agonist. - In Study 3 and Study 4, the primary measure of effectiveness was the change in the mean number of hours spent in the “OFF” state at baseline compared to the mean number of hours spent in the “OFF” state during the treatment period. - In Study 3, patients were randomly assigned to receive placebo (159 patients), AZILECT 0.5 mg/day (164 patients), or AZILECT 1 mg/day (149 patients) for 26 weeks. Patients averaged 6 hours daily in the “OFF” state at baseline as confirmed by home diaries. - In Study 4, patients were randomly assigned to receive placebo (229 patients), AZILECT 1 mg/day (231 patients) or a COMT inhibitor (active comparator), taken along with scheduled doses of levodopa/decarboxylase inhibitor (227 patients) for 18 weeks. Patients averaged 5.6 hours daily in the “OFF” state at baseline as confirmed by home diaries. - In Study 3 and Study 4, AZILECT 1 mg once daily reduced “OFF” time compared to placebo when added to levodopa in patients experiencing motor fluctuations (Tables 7 and 8). The lower dose (0.5 mg) of AZILECT also significantly reduced “OFF” time (Table 7), but had a numerically smaller effect than the 1 mg dose of AZILECT. In Study 4, the active comparator also reduced “OFF” time when compared to placebo. - In Study 3 and Study 4, dose reduction of levodopa was allowed within the first 6 weeks, if dopaminergic side effects developed including dyskinesia or hallucinations. In Study 3, the levodopa dose was reduced in 8% of patients in the placebo group and in 16% and 17% of patients in the 0.5 mg/day and 1 mg/day AZILECT groups, respectively. When levodopa was reduced, the dose was reduced by 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In Study 4, levodopa dose reduction occurred in 6% of patients in the placebo group and in 9% in the AZILECT 1 mg/day groups, respectively. When levodopa was reduced, it was reduced by 13% and 11% in the placebo and the AZILECT groups, respectively. - There were no differences in effectiveness based on age or gender between AZILECT 1 mg/day and placebo. - Several secondary outcome assessments in the two studies showed statistically significant improvements with rasagiline. These included effects on the activities of daily living (ADL) subscale of the UPDRS performed during an “OFF” period and the motor subscale of the UPDRS performed during an “ON” period. In both scales, a negative response represents improvement. Tables 9 and 10 show these results for Studies 3 and 4. # How Supplied - AZILECT 0.5 mg Tablets: - White to off-white, round, flat, beveled tablets, debossed with “GIL 0.5” on one side and plain on the other side. Supplied as bottles of 30 tablets (NDC 68546-142-56). - AZILECT 1 mg Tablets: - White to off-white, round, flat, beveled tablets, debossed with “GIL 1” on one side and plain on the other side. Supplied as bottles of 30 tablets (NDC 68546-229-56). - Storage: - Store at 25°C (77°F) with excursions permitted to 15°-30°C (59°-86°F). ## Storage There is limited information regarding Rasagiline Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Hypertension - Advise patients that treatment with recommended doses of AZILECT may be associated with elevations of blood pressure. Tell patients who experience elevation of blood pressure while taking AZILECT to contact their healthcare provider. - The risk of using higher than recommended daily doses of AZILECT should be explained, and a brief description of the tyramine associated hypertensive reaction provided. - Advise patients to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of AZILECT because of the potential for large increases in blood pressure. If patients eat foods very rich in tyramine and do not feel well soon after eating, they should contact their healthcare provider [see Warnings and Precautions (5.1)]. - Serotonin Syndrome - Tell patients to inform their physician if they are taking, or planning to take, any prescription or over-the-counter drugs, especially antidepressants and over-the-counter cold medications, since there is a potential for interaction with AZILECT. Because patients should not use meperidine or certain other analgesics with AZILECT, they should contact their healthcare provider before taking analgesics [see Contraindications (4) and Warnings and Precautions (5.2)]. - Falling Asleep During Activities of Daily Living and Somnolence - Advise and alert patients about the potential for sedating effects associated with AZILECT and other dopaminergic medications, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with AZILECT and other dopaminergic medications to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of AZILECT. - Because of possible additive effects, advise patients to exercise caution when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants) in combination with AZILECT or when taking concomitant medications that increase plasma levels of rasagiline (e.g., ciprofloxacin) [see Warnings and Precautions (5.3)]. - Ciprofloxacin or Other CYP1A2 Inhibitors - Inform patients that they should contact their healthcare provider of AZILECT if they take ciprofloxacin or a similar drug that could increase blood levels of rasagiline because of the need to adjust the dose of AZILECT [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. - Hepatic Impairment - Tell patients who have hepatic problems to contact their healthcare provider regarding possible changes in AZILECT dosing [see Warnings and Precautions (5.5)]. - Hypotension / Orthostatic Hypotension - Patients should be advised that they may develop orthostatic hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment). Accordingly, patients should be cautioned against standing up rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially, at the initiation of treatment with AZILECT [see Warnings and Precautions (5.6)]. - Dyskinesia - Advise patients taking AZILECT as adjunct to levodopa that there is a possibility of dyskinesia or increased dyskinesia [see Warnings and Precautions (5.7)]. - Hallucinations / Psychotic-Like Behavior - Inform patients that hallucinations or other manifestations of psychotic-like behavior can occur when taking AZILECT. Advise patients that, if they have a major psychotic disorder, that AZILECT should not ordinarily be used because of the risk of exacerbating the psychosis. Patients with a major psychotic disorder should also be aware that many treatments for psychosis may decrease the effectiveness of AZILECT [see Warnings and Precautions (5.8)]. - Impulse Control/Compulsive Behaviors - Advise patients that they may experience intense urges to gamble, increased sexual urges, other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease (including AZILECT). Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges, or other urges while being treated with AZILECT. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges, or other intense urges while taking AZILECT. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking AZILECT [see Warnings and Precautions (5.9)]. - Withdrawal-Emergent Hyperpyrexia and Confusion - Tell patients to contact their healthcare provider if they wish to discontinue AZILECT [see Warnings and Precautions (5.10)]. - Missing Dose - Instruct patients to take AZILECT as prescribed. If a dose is missed, the patient should not double-up the dose of AZILECT. The next dose should be taken at the usual time on the following day. # Precautions with Alcohol - Alcohol-Rasagiline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - AZILECT®[1] # Look-Alike Drug Names - Azilect® — Aricept®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Azilect
16b4cc252003dc52ab25c0dcc52c0b0a11467c0d	wikidoc	Azlocillin	Azlocillin # Overview Azlocillin is an acylampicillin antibiotic with an extended spectrum of activity and greater in vitro potency than the carboxy penicillins. Azlocillin is similar to mezlocillin and piperacillin. It demonstrates antibacterial activity against a broad spectrum of bacteria, including Pseudomonas aeruginosa and, in contrast to most cephalosporins, exhibits activity against enterococci. # Spectrum of bacterial susceptibility Azlocillin is considered a broad spectrum antibiotic and can be used against a number of Gram positive and Gram negative bacteria. The following represents MIC susceptibility data for a few medically significant organisms. - Escherichia coli 1 μg/mL - 32 μg/mL - Haemophilus spp. 0.03 μg/mL - 2 μg/mL - Pseudomonas aeruginosa 4 μg/mL - 6.25 μg/mL	Azlocillin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Azlocillin is an acylampicillin antibiotic with an extended spectrum of activity and greater in vitro potency than the carboxy penicillins. Azlocillin is similar to mezlocillin and piperacillin. It demonstrates antibacterial activity against a broad spectrum of bacteria, including Pseudomonas aeruginosa and, in contrast to most cephalosporins, exhibits activity against enterococci. # Spectrum of bacterial susceptibility Azlocillin is considered a broad spectrum antibiotic and can be used against a number of Gram positive and Gram negative bacteria. The following represents MIC susceptibility data for a few medically significant organisms.[1] - Escherichia coli 1 μg/mL - 32 μg/mL - Haemophilus spp. 0.03 μg/mL - 2 μg/mL - Pseudomonas aeruginosa 4 μg/mL - 6.25 μg/mL	https://www.wikidoc.org/index.php/Azlocillin
2a76e08dd518dd3a3381e50b95682c63016212d9	wikidoc	B vitamins	B vitamins # Overview The B vitamins are eight water-soluble vitamins that play important roles in cell metabolism. Historically, the B vitamins were once thought to be a single vitamin, referred to as vitamin B (much like how people refer to vitamin C or vitamin D). Later research showed that they are chemically distinct vitamins that often coexist in the same foods. Supplements containing all eight B vitamins are generally referred to as a vitamin B complex. Individual B vitamin supplements are referred to by the specific name of each vitamin (e.g. B1, B2, B3). # List of B vitamins - Vitamin B1 (thiamine) - Vitamin B2 (riboflavin) - Vitamin B3,(niacin, includes nicotinic acid and nicotinamide) - Vitamin B5 (pantothenic acid) - Vitamin B6 (pyridoxine) - Vitamin B7, also called vitamin H (biotin) - Vitamin B9, also vitamin M and vitamin B-c (folic acid) - Vitamin B12 (cyanocobalamin) - Vitamin B8 (myo-inositol) is no longer classified as a vitamin because it is synthesized by the human body # B vitamin deficiency Several named vitamin deficiency diseases may result from the lack of sufficient B-vitamins. Deficiencies of other B vitamins result in symptoms that are not part of a named deficiency disease. # Related nutrients Many of the following substances have been referred to as vitamins because they were believed to be vitamins at one time, and they are relevant to vitamin nomenclature in that the numbers that were assigned to them form "gaps" in the series of B-vitamin names. Some of them, though not essential to humans, are essential in the diets of other organisms; others have no known nutritional value. While they are non-"essential" in that they may be synthesized by the body from other starting materials, they have dietary significance. See also Orthomolecular medicine. - Vitamin B4: Adenine, a nucleobase. - Vitamin B7: "Vitamin I" of Centanni E. (1935) — also called 'Enteral factor' — is a water and alcohol soluble rice-bran factor which prevents digestive disturbance in pigeons. It governs the anatomical and functional integrity of the intestinal tract. Later found in yeast. Possible candidates for this substance are inositol, niacin (nicotinic acid), and biotin. Carnitine was also claimed to be a candidate but is not soluble in alcohol. - Vitamin B8: adenosine monophosphate, or alternately inositol has also been called vitamin B8 - Vitamin B10: para-aminobenzoic acid, or PABA - Vitamin B11: Pteryl-hepta-glutamic acid – Chick growth factor, which is a form of Folic acid. Later found to be one of five folates necessary for humans; (L-carnitine) is called Vitamin B11 in France. - Vitamin B13: Orotic acid. - Vitamin B14: cell proliferant, anti-anemia, rat growth, and antitumor pterin phosphate named by Earl R. Norris (biochemist of folic acid fame). Isolated from human urine at 0.33ppm (later in blood), but later abandoned by him as further evidence did not confirm this. He also claimed this was not Xanthopterin. - Vitamin B15 6-O-(dimethylaminoacetyl)-D-gluconic acid (Pangamic acid) - Vitamin B16 (dimethylglycine) – also known as DMG. (However Lipoic acid was discovered and named a B-Vitamin after B15 and before B17) - Vitamin B17 (Amygdalin, Nitrilosides, or laetrile) – A substance found in a number of seeds, sprouts, beans, tubers and grains. While toxic in large quantities, proponents claim that it is effective in cancer treatment and prevention. - Vitamin B18 – - Vitamin B19 – - Vitamin B20 (Carnitine) – - Vitamin B21 – - Vitamin B22 – often claimed as an ingredient of Aloe vera extracts but also in many other foods. Claimed by one source to be Vitamin B12b-δ. - Vitamin Bh – another name for Biotin - Vitamin Bm ("mouse factor") – also used to designate Inositol - Vitamin Bp (Choline) – - Vitamin Bt (L-carnitine) – - Vitamin Bv – a type of B6 but not Pyridoxine - Vitamin Bw – a type of Biotin but not d-Biotin - Vitamin Bx – another name for PABA (para-Aminobenzoic acid) - Lipoic acid – Note: B16, B17, B18, B19, B20, B21 & B22 do not appear to be animal factors but are claimed by naturopaths as human therapedic factors. # Health benefits The B vitamins often work together to deliver a number of health benefits to the body. B vitamins have been shown to: - Support and increase the rate of metabolism - Maintain healthy skin and muscle tone - Enhance immune and nervous system function - Promote cell growth and division — including that of the red blood cells that help prevent anemia. Together, they also help combat the symptoms and causes of stress, depression, and cardiovascular disease. All B vitamins are water soluble, and are dispersed throughout the body. Most of the B vitamins must be replenished daily, since any excess is excreted in the urine. A six year cobalamin store can be found in the liver, despite its water soluble nature. # Vitamin B sources Vitamin B comes from a number of natural sources, including potatoes, bananas, lentils, chilli peppers, tempeh, liver oil, liver, turkey, and tuna. Nutritional yeast (or brewer's yeast) and molasses are especially good sources of Vitamin B. Marmite and the iconic Australian spread Vegemite bills itself as "one of the world's richest known sources of vitamin B". As might be expected, due to its high content of brewer's yeast, beer is a good source of B vitamins--in fact, beer is sometimes referred to as "liquid bread"--although this may be less true for filtered beersand the alcohol in beer impairs the body's ability to activate vitamins. Another popular means of increasing one's Vitamin B intake is through the use of dietary supplements purchased at supermarkets, health centers, or natural food stores. B vitamins are also commonly added to energy drinks. # Mnemonic One mnemonic to remember the most commonly referenced B vitamins is "The (B1, Thiamine) Rhythm (B2, Riboflavin) Nearly (B3, Niacin) Proved (B6, Pyridoxin) Contagious (B12, Cobalamin)".	B vitamins Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview The B vitamins are eight water-soluble vitamins that play important roles in cell metabolism. Historically, the B vitamins were once thought to be a single vitamin, referred to as vitamin B (much like how people refer to vitamin C or vitamin D). Later research showed that they are chemically distinct vitamins that often coexist in the same foods. Supplements containing all eight B vitamins are generally referred to as a vitamin B complex. Individual B vitamin supplements are referred to by the specific name of each vitamin (e.g. B1, B2, B3). # List of B vitamins - Vitamin B1 (thiamine) - Vitamin B2 (riboflavin) - Vitamin B3,(niacin, includes nicotinic acid and nicotinamide) - Vitamin B5 (pantothenic acid) - Vitamin B6 (pyridoxine) - Vitamin B7, also called vitamin H (biotin) - Vitamin B9, also vitamin M and vitamin B-c (folic acid) - Vitamin B12 (cyanocobalamin) - Vitamin B8 (myo-inositol) is no longer classified as a vitamin because it is synthesized by the human body # B vitamin deficiency Several named vitamin deficiency diseases may result from the lack of sufficient B-vitamins. Deficiencies of other B vitamins result in symptoms that are not part of a named deficiency disease. # Related nutrients Many of the following substances have been referred to as vitamins because they were believed to be vitamins at one time, and they are relevant to vitamin nomenclature in that the numbers that were assigned to them form "gaps" in the series of B-vitamin names. Some of them, though not essential to humans, are essential in the diets of other organisms; others have no known nutritional value. While they are non-"essential" in that they may be synthesized by the body from other starting materials, they have dietary significance. See also Orthomolecular medicine. - Vitamin B4: Adenine, a nucleobase.[1] - Vitamin B7: "Vitamin I" of Centanni E. (1935) — also called 'Enteral factor' — is a water and alcohol soluble rice-bran factor which prevents digestive disturbance in pigeons. It governs the anatomical and functional integrity of the intestinal tract. Later found in yeast. Possible candidates for this substance are inositol, niacin (nicotinic acid), and biotin. Carnitine was also claimed to be a candidate but is not soluble in alcohol. - Vitamin B8: adenosine monophosphate, or alternately inositol has also been called vitamin B8 - Vitamin B10: para-aminobenzoic acid, or PABA - Vitamin B11: Pteryl-hepta-glutamic acid – Chick growth factor, which is a form of Folic acid. Later found to be one of five folates necessary for humans; (L-carnitine) is called Vitamin B11 in France. - Vitamin B13: Orotic acid. - Vitamin B14: cell proliferant, anti-anemia, rat growth, and antitumor pterin phosphate named by Earl R. Norris (biochemist of folic acid fame). Isolated from human urine at 0.33ppm (later in blood), but later abandoned by him as further evidence did not confirm this. He also claimed this was not Xanthopterin. - Vitamin B15 6-O-(dimethylaminoacetyl)-D-gluconic acid (Pangamic acid) - Vitamin B16 (dimethylglycine) – also known as DMG. (However Lipoic acid was discovered and named a B-Vitamin after B15 and before B17) - Vitamin B17 (Amygdalin, Nitrilosides, or laetrile) – A substance found in a number of seeds, sprouts, beans, tubers and grains. While toxic in large quantities, proponents claim that it is effective in cancer treatment and prevention. [2] - Vitamin B18 – - Vitamin B19 – - Vitamin B20 (Carnitine) – - Vitamin B21 – - Vitamin B22 – often claimed as an ingredient of Aloe vera extracts but also in many other foods. Claimed by one source to be Vitamin B12b-δ. - Vitamin Bh – another name for Biotin - Vitamin Bm ("mouse factor") – also used to designate Inositol - Vitamin Bp (Choline) – - Vitamin Bt (L-carnitine) – - Vitamin Bv – a type of B6 but not Pyridoxine - Vitamin Bw – a type of Biotin but not d-Biotin - Vitamin Bx – another name for PABA (para-Aminobenzoic acid) - Lipoic acid – Note: B16, B17, B18, B19, B20, B21 & B22 do not appear to be animal factors but are claimed by naturopaths as human therapedic factors. # Health benefits The B vitamins often work together to deliver a number of health benefits to the body. B vitamins have been shown to: - Support and increase the rate of metabolism - Maintain healthy skin and muscle tone - Enhance immune and nervous system function - Promote cell growth and division — including that of the red blood cells that help prevent anemia. Together, they also help combat the symptoms and causes of stress, depression, and cardiovascular disease. All B vitamins are water soluble, and are dispersed throughout the body. Most of the B vitamins must be replenished daily, since any excess is excreted in the urine.[3] A six year cobalamin store can be found in the liver, despite its water soluble nature. # Vitamin B sources Vitamin B comes from a number of natural sources, including potatoes, bananas, lentils, chilli peppers, tempeh, liver oil, liver, turkey, and tuna. Nutritional yeast (or brewer's yeast) and molasses are especially good sources of Vitamin B. Marmite and the iconic Australian spread Vegemite bills itself as "one of the world's richest known sources of vitamin B". As might be expected, due to its high content of brewer's yeast, beer is a good source of B vitamins[4]--in fact, beer is sometimes referred to as "liquid bread"[5]--although this may be less true for filtered beers[6]and the alcohol in beer impairs the body's ability to activate vitamins. Another popular means of increasing one's Vitamin B intake is through the use of dietary supplements purchased at supermarkets, health centers, or natural food stores. B vitamins are also commonly added to energy drinks. # Mnemonic One mnemonic to remember the most commonly referenced B vitamins is "The (B1, Thiamine) Rhythm (B2, Riboflavin) Nearly (B3, Niacin) Proved (B6, Pyridoxin) Contagious (B12, Cobalamin)".[7]	https://www.wikidoc.org/index.php/B-vitamins
a929de50da259a6ff7c9222f1a42c291c768f005	wikidoc	BBX (gene)	BBX (gene) HMG box transcription factor BBX also known as bobby sox homolog or HMG box-containing protein 2 is a protein that in humans is encoded by the BBX gene. # Model organisms Model organisms have been used in the study of BBX function. A conditional knockout mouse line, called Bbxtm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on homozygous mutant adult mice and four significant abnormalities were observed. A study of body composition found decreases in bone mineral density and content, and a reduction in body length in female mice, while mutants of both sexes showed a reduction in lean body mass. Radiography found that males had abnormal teeth morphology. Females had a decreased heart weight, and both sexes had reduced IgA levels in their plasma.	BBX (gene) HMG box transcription factor BBX also known as bobby sox homolog or HMG box-containing protein 2 is a protein that in humans is encoded by the BBX gene.[1] # Model organisms Model organisms have been used in the study of BBX function. A conditional knockout mouse line, called Bbxtm1a(EUCOMM)Wtsi[10][11] was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[12][13][14] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty six tests were carried out on homozygous mutant adult mice and four significant abnormalities were observed.[8] A study of body composition found decreases in bone mineral density and content, and a reduction in body length in female mice, while mutants of both sexes showed a reduction in lean body mass. Radiography found that males had abnormal teeth morphology. Females had a decreased heart weight, and both sexes had reduced IgA levels in their plasma.[8]	https://www.wikidoc.org/index.php/BBX_(gene)
41a0a986a1498e6d222e24888e20ae7d420d8d4d	wikidoc	BCR (gene)	BCR (gene) The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL complex, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene. # Function Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The protein has serine/threonine kinase activity and is a guanine nucleotide exchange factor for Rho family GTPases including RhoA. # Clinical significance A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with chronic myelogenous leukemia. The chromosome 22 breakpoint for this translocation is located within the BCR gene. The translocation produces a fusion protein that is encoded by sequence from both BCR and ABL, the gene at the chromosome 9 breakpoint. # Structure The BCR-ABL oncoprotein oligomerisation domain found at the N-terminus of BCR is essential for the oncogenicity of the BCR-ABL fusion protein. The BCR-ABL oncoprotein oligomerisation domain consists of a short N-terminal helix (alpha-1), a flexible loop and a long C-terminal helix (alpha-2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the alpha-2 helices and domain swapping of two alpha-1 helices, where one alpha-1 helix swings back and packs against the alpha-2 helix from the second monomer. Two dimers then associate into a tetramer. # Interactions The BCR protein has been shown to interact with: - Abl gene, - CD117, - CRKL - FES, - Grb2, - GRB10, - HCK, - MLLT4, - PXN, - PIK3CG, - PTPN6, - PTPRT(PTPrho) - SOS1, and - XPB.	BCR (gene) The breakpoint cluster region protein (BCR) also known as renal carcinoma antigen NY-REN-26 is a protein that in humans is encoded by the BCR gene. BCR is one of the two genes in the BCR-ABL complex, which is associated with the Philadelphia chromosome. Two transcript variants encoding different isoforms have been found for this gene. # Function Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The protein has serine/threonine kinase activity and is a guanine nucleotide exchange factor for Rho family GTPases including RhoA.[1][2] # Clinical significance A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with chronic myelogenous leukemia. The chromosome 22 breakpoint for this translocation is located within the BCR gene. The translocation produces a fusion protein that is encoded by sequence from both BCR and ABL, the gene at the chromosome 9 breakpoint.[3] # Structure The BCR-ABL oncoprotein oligomerisation domain found at the N-terminus of BCR is essential for the oncogenicity of the BCR-ABL fusion protein. The BCR-ABL oncoprotein oligomerisation domain consists of a short N-terminal helix (alpha-1), a flexible loop and a long C-terminal helix (alpha-2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the alpha-2 helices and domain swapping of two alpha-1 helices, where one alpha-1 helix swings back and packs against the alpha-2 helix from the second monomer. Two dimers then associate into a tetramer.[4] # Interactions The BCR protein has been shown to interact with: - Abl gene,[5][6][7] - CD117,[8] - CRKL[9][10][11][12] - FES,[13][14] - Grb2,[5][9][10][14][15][16] - GRB10,[9] - HCK,[17][18] - MLLT4,[19] - PXN,[20][21] - PIK3CG,[9][20][22] - PTPN6,[23] - PTPRT(PTPrho)[24] - SOS1,[5][14] and - XPB.[25]	https://www.wikidoc.org/index.php/BCR_(gene)
8a251fe5a39d511031e2490841ebc7eb5d90712a	wikidoc	Neuropilin	Neuropilin Neuropilin is a protein receptor active in neurons. There are two forms of Neuropilins, NRP-1 and NRP-2. They are transmembrane glycoproteins, and predominantly co-receptors for another class of proteins known as semaphorins. Of the semaphorins, NRP-1 and NRP-2 are specifically receptors for class-3 semaphorins, which, among many things, are responsible for axon guidance during the development of the nervous system in vertebrates. Neuropilins work as co-receptors as they have a very small cytoplasmic domain and thus rely upon other molecules (normally plexins) to transduce their signals across a cell membrane. Neuropilins generally work as dimers and different combinations have different affinities for molecules. For example, NRP-1 homodimers have high affinity for Sema3A, whilst NRP-2 homodimers have high affinity for Sema3F. Another ligand for neuropilins is VEGF, a growth factor involved in the regulation of angiogenesis. The pleiotropic nature of the NRP receptors results in their involvement in multiple signalling pathways, such as axon guidance and angiogenesis, the immune response and remyelination. # Applications Neuropilin-1 is a therapeutic target protein in the treatment for leukemia and lymphoma, since It has been shown that there is increased expression in neuropilin-1 in leukemia and lymphoma cell lines. Also, antagonism of neuropilin-1 has been found to inhibit tumour cell migration and adhesion. # Structure Neuropilins contain the following four domains: - N-terminal CUB domain (for complement C1r/C1s, Uegf, Bmp1) - Coagulation factor 5/8 type, C-terminal (discoidin domain) - MAM domain (for meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu) - C-terminal neuropilin The structure of B1 domain (coagulation factor 5/8 type) of neuropilin-1 was determined through X-Ray Diffraction with a resolution of 2.90 Å. The secondary structure of this domain is 5% alpha helical and 46% beta sheet. Ramachandran plot.	Neuropilin Neuropilin is a protein receptor active in neurons. There are two forms of Neuropilins, NRP-1 and NRP-2. They are transmembrane glycoproteins, and predominantly co-receptors for another class of proteins known as semaphorins. Of the semaphorins, NRP-1 and NRP-2 are specifically receptors for class-3 semaphorins, which, among many things, are responsible for axon guidance during the development of the nervous system in vertebrates. Neuropilins work as co-receptors as they have a very small cytoplasmic domain and thus rely upon other molecules (normally plexins) to transduce their signals across a cell membrane. Neuropilins generally work as dimers and different combinations have different affinities for molecules. For example, NRP-1 homodimers have high affinity for Sema3A, whilst NRP-2 homodimers have high affinity for Sema3F. Another ligand for neuropilins is VEGF, a growth factor involved in the regulation of angiogenesis. The pleiotropic nature of the NRP receptors results in their involvement in multiple signalling pathways, such as axon guidance and angiogenesis, the immune response and remyelination.[2] # Applications Neuropilin-1 is a therapeutic target protein in the treatment for leukemia and lymphoma, since It has been shown that there is increased expression in neuropilin-1 in leukemia and lymphoma cell lines.[3] Also, antagonism of neuropilin-1 has been found to inhibit tumour cell migration and adhesion.[4] # Structure Neuropilins contain the following four domains: - N-terminal CUB domain (for complement C1r/C1s, Uegf, Bmp1) - Coagulation factor 5/8 type, C-terminal (discoidin domain) - MAM domain (for meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu) - C-terminal neuropilin The structure of B1 domain (coagulation factor 5/8 type) of neuropilin-1 was determined through X-Ray Diffraction with a resolution of 2.90 Å. The secondary structure of this domain is 5% alpha helical and 46% beta sheet.[1] Ramachandran plot.[5]	https://www.wikidoc.org/index.php/BDCA-4
8a878b51985f89541723dba77e761df1b311176a	wikidoc	BET theory	BET theory # Overview BET theory is a well-known rule for the physical adsorption of gas molecules on a solid surface, that is basis for an important analysis technique for the measurement of the specific surface area of a material. In 1938, Stephen Brunauer, Paul Hugh Emmett, and Edward Teller published an article about the BET theory in a journal for the first time; “BET” consists of the first initials of their family names. The concept of the theory is an extension of the Langmuir theory, which is a theory for monolayer molecular adsorption, to multilayer adsorption with the following hypotheses: (a) gas molecules physically adsorb on a solid in layers infinitely; (b) there is no interaction between each adsorption layer; and (c) the Langmuir theory can be applied to each layer. The resulting BET equation is expressed by (1): P and P_0 are the equilibrium and the saturation pressure of adsorbates at the temperature of adsorption, v is the adsorbed gas quantity (for example, in volume units), and v_m is the monolayer adsorbed gas quantity. c is the BET constant, which is expressed by (2): E_1 is the heat of adsorption for the first layer, and E_L is that for the second and higher layers and is equal to the heat of liquefaction. Equation (1) is an adsorption isotherm and can be plotted as a straight line with {1}/{v } on the y-axis and \phi={P}/{P_0} on the x-axis according to experimental results. This plot is called a BET plot. The linear relationship of this equation is maintained only in the range of 0.05 . The value of the slope A and the y-intercept I of the line are used to calculate the monolayer adsorbed gas quantity v_m and the BET constant c. The following equations can be used: The BET method is widely used in surface science for the calculation of surface areas of solids by physical adsorption of gas molecules. A total surface area S_{total} and a specific surface area S are evaluated by the following equations: # Examples ## Cement paste By application of the BET theory it is possible to determine the inner surface of hardened cement paste. If the quantity of adsorbed water vapour is measured at different levels of relative humidity a BET plot is obtained. From the slope A and y-intersection I on the plot it is possible to calculate v_m and the BET constant c. In case of cement paste hardened in water (T=97°C), the slope of the line is A=24.20 and the y-intersection I=0.33; from this follows From this the specific BET surface area S_{BET} can be calculated by use of the above mentioned equation (one water molecule covers s=0.114 nm^2). It follows thus S_{BET} = 156 m^2/g which means that hardened cement paste has an inner surface of 156 square meters per g of cement. ## Activated Carbon For example, activated carbon, which is a strong adsorbate and usually has an adsorption cross section s of 0.16 nm2 for nitrogen adsorption at liquid nitrogen temperature, is revealed from experimental data to have a large surface area around 3000 m² g-1. Moreover, in the field of solid catalysis, the surface area of catalysts is an important factor in catalytic activity. Porous inorganic materials such as mesoporous silica and layer clay minerals have high surface areas of several hundred m² g-1 calculated by the BET method, indicating the possibility of application for efficient catalytic materials.	BET theory Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview BET theory is a well-known rule for the physical adsorption of gas molecules on a solid surface, that is basis for an important analysis technique for the measurement of the specific surface area of a material. In 1938, Stephen Brunauer, Paul Hugh Emmett, and Edward Teller published an article about the BET theory in a journal[1] for the first time; “BET” consists of the first initials of their family names. The concept of the theory is an extension of the Langmuir theory, which is a theory for monolayer molecular adsorption, to multilayer adsorption with the following hypotheses: (a) gas molecules physically adsorb on a solid in layers infinitely; (b) there is no interaction between each adsorption layer; and (c) the Langmuir theory can be applied to each layer. The resulting BET equation is expressed by (1): <math>P</math> and <math>P_0</math> are the equilibrium and the saturation pressure of adsorbates at the temperature of adsorption, <math>v</math> is the adsorbed gas quantity (for example, in volume units), and <math>v_m</math> is the monolayer adsorbed gas quantity. <math>c</math> is the BET constant, which is expressed by (2): <math>E_1</math> is the heat of adsorption for the first layer, and <math>E_L</math> is that for the second and higher layers and is equal to the heat of liquefaction. Equation (1) is an adsorption isotherm and can be plotted as a straight line with <math> {1}/{v [ ({P_0}/{P}) -1 ]}</math> on the y-axis and <math> \phi={P}/{P_0} </math> on the x-axis according to experimental results. This plot is called a BET plot. The linear relationship of this equation is maintained only in the range of <math>0.05 < {P}/{P_0} < 0.35</math>. The value of the slope <math>A</math> and the y-intercept <math>I</math> of the line are used to calculate the monolayer adsorbed gas quantity <math>v_m</math> and the BET constant <math>c</math>. The following equations can be used: The BET method is widely used in surface science for the calculation of surface areas of solids by physical adsorption of gas molecules. A total surface area <math>S_{total}</math> and a specific surface area <math>S</math> are evaluated by the following equations: # Examples ## Cement paste By application of the BET theory it is possible to determine the inner surface of hardened cement paste. If the quantity of adsorbed water vapour is measured at different levels of relative humidity a BET plot is obtained. From the slope <math>A</math> and y-intersection <math>I</math> on the plot it is possible to calculate <math>v_m</math> and the BET constant <math>c</math>. In case of cement paste hardened in water (T=97°C), the slope of the line is <math>A=24.20</math> and the y-intersection <math>I=0.33</math>; from this follows From this the specific BET surface area <math>S_{BET}</math> can be calculated by use of the above mentioned equation (one water molecule covers <math>s=0.114 nm^2</math>). It follows thus <math>S_{BET} = 156 m^2/g</math> which means that hardened cement paste has an inner surface of 156 square meters per g of cement. ## Activated Carbon For example, activated carbon, which is a strong adsorbate and usually has an adsorption cross section <math>s</math> of 0.16 nm2 for nitrogen adsorption at liquid nitrogen temperature, is revealed from experimental data to have a large surface area around 3000 m² g-1. Moreover, in the field of solid catalysis, the surface area of catalysts is an important factor in catalytic activity. Porous inorganic materials such as mesoporous silica and layer clay minerals have high surface areas of several hundred m² g-1 calculated by the BET method, indicating the possibility of application for efficient catalytic materials.	https://www.wikidoc.org/index.php/BET_theory
27a3f67790ef6fbb8c07bf74ffafd9e71c08d4a1	wikidoc	BK channel	BK channel BK channels (Big Potassium), also known as Maxi-K, slo1, or Kca1.1, are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the cell membrane, hence their name, Big Potassium. These channels can be activated (opened) by either electrical means, or by increasing calcium concentrations in the cell. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels. # Structure Structurally, BK channels are homologous to voltage- and ligand-gated potassium channels, having a voltage sensor and pore as the membrane-spanning domain and a cytosolic domain for the binding of intracellular calcium and magnesium. Each monomer of the channel-forming alpha subunit is the product of the KCNMA1 gene (also known as Slo1). The Slo1 subunit has three main structural domains, each with a distinct function: the vvoltage sensing domain (VSD) senses membrane potential across the membrane, the cytosolic domain (senses calcium concentration, Ca²⁺ ions), and the pore-gate domain (PGD) which opens and closes to regulate potassium permeation. The activation gate resides in the PGD, which is located at either the cytosolic side of S6 or the selectivity filter (selectivity is the preference of a channel to conduct a specific ion). The Voltage sensing domain and pore-gated domain are collectively referred as the membrane-spanning domains and are formed by transmembrane segments S1-S4 and S5-S6, respectively. Within the S4 helix contains a series of positively charged residues which serve as the primary voltage sensor. BK channels are quite similar to voltage gated K⁺ channels, however, in BK channels only one positively charged residue (Arg213) is involved in voltage sensing across the membrane. Also unique to BK channels is an additional S0 segment, this segment is required for β subunit modulation. and voltage sensitivity. The Cytosolic domain is composed of two RCK (regulator of potassium conductance) domains, RCK1 and RCK2. These domains contain two high affinity Ca²⁺ binding sites: one in the RCK1 domain and the other in a region termed the Ca²⁺ bowl that consists of a series of Aspartic acid (Asp) residues that are located in the RCK2 domain. The Mg²⁺ binding site is located between the VSD and the cytosolic domain, which is formed by: Asp residues within the S0-S1 loop, Asparagine residues in the cytosolic end of S2, and Glutamine residues in RCK1. In forming the Mg²⁺ binding site, two residues come from the RCK1 of one Slo1 subunit and the other two residues come from the VSD of the neighboring subunit. In order for these residues to coordinate the Mg²⁺ ion, the VSD and cytosolic domain from neighboring subunits must be in close proximity. Modulatory beta subunits (encoded by KCNMB1, KCNMB2, KCNMB3, or KCNMB4) can associate with the tetrameric channel. There are four types of β subunits (β1-4), each of which have different expression patterns that modify the gating properties of the BK channel. The β1 subunit is primarily responsible for smooth muscle cell expression, both β2 and β3 subunits are neuronally expressed, while β4 is expressed within the brain. The VSD associates with the PGD via three major interactions: - Physical connection between the VSD and PGD through the S4-S5 linker. - Interactions between the S4-S5 linker and the cytosolic side of S6. - Interactions between S4 and S5 of a neighboring subunit. # Regulation BK channels are associated and modulated by a wide variety of intra- and extracellular factors, such as auxiliary subunits (β, γ), Slobs (slo binding protein), phosphorylation, membrane voltage, chemical ligands (Ca²⁺, Mg²⁺), PKC, The BK α-subunits assemble 1:1 with four different auxiliary types of β-subunits (β1, β2, β3 or β4). Trafficking to and expression of BK channels in the plasma membrane has been found to be regulated by distinct splicing motifs located within the intracellular C-terminal RCK domains. In particular a splice variant that excluded these motifs prevented cell surface expression of BK channels and suggests that such a mechanism impacts physiology and pathophysiology. BK channels in the vascular system are modulated by agents naturally produced in the body, such as angiotensin II (Ang II), high glucose or arachidonic acid (AA) which is modulated in diabetes by oxidative stress (ROS). A weaker voltage sensitivity allows BK channels to function in a wide range of membrane potentials. This ensures that the channel can properly perform its physiological function. Inhibition of BK channel activity by phosphorylation of S695 by protein kinase C (PKC) is dependent on the phosphorylation of S1151 in C terminus of channel alpha-subunit. Only one of these phosphorylations in the tetrameric structure needs to occur for inhibition to be successful. Protein phosphatase 1 counteracts phosphorylation of S695. PKC decreases channel opening probability by shortening the channel open time and prolonging the closed state of the channel. PKC does not affect the single-channel conductance, voltage dependence, or the calcium sensitivity of BK channels. # Activation mechanism BK channels are synergistically activated through the binding of calcium and magnesium ions, but can also be activated via voltage dependence. Ca²⁺ - dependent activation occurs when intracellular Ca²⁺ binds to two high affinity binding sites: one located in the C-terminus of the RCK2 domain (Ca²⁺ bowl), and the other located in the RCK1 domain. The binding site within the RCK1 domain has somewhat of a lower affinity for calcium than the Ca²⁺ bowl, but is responsible for a larger portion of the Ca²⁺ sensitivity. Voltage and calcium activate BK channels using two parallel mechanisms, with the voltage sensors and the Ca²⁺ bindings sites coupling to the activation gate independently, except for a weak interaction between the two mechanisms. The Ca²⁺ bowl accelerates activation kinetics at low Ca²⁺ concentrations while RCK1 site influences both activation and deactivation kinetics. One mechanism model was originally proposed by Monod, Wyman, and Changeux, known as the MWC model. The MWC model for BK channels explains that a conformational change of the activation gate in channel opening is accompanied by a conformational change to the Ca²⁺ binding site, which increases the affinity of Ca²⁺ binding. Magnesium-dependent activation of BK channels activates via a low-affinity metal binding site that is independent from Ca²⁺-dependent activation. The Mg²⁺ sensor activates BK channels by shifting the activation voltage to a more negative range. Mg²⁺ activates the channel only when the voltage sensor domain stays in the activated state. The cytosolic tail domain (CTD) is a chemical sensor that has multiple binding sites for different ligands. The CTD activates the BK channel when bound with intracellular Mg²⁺ to allow for interaction with the voltage sensor domain (VSD). Magnesium is predominantly coordinated by six oxygen atoms from the side chains of oxygen-containing residues, main chain carbonyl groups in proteins, or water molecules. D99 at the C-terminus of the S0-S1 loop and N172 in the S2-S3 loop contain side chain oxygens in the voltage sensor domain that are essential for Mg²⁺ binding. Much like the Ca²⁺-dependent activation model, Mg²⁺-dependent activation can also be described by an allosteric MCW gating model. While calcium activates the channel largely independent of the voltage sensor, magnesium activates the channel by channel by an electrostatic interaction with the voltage sensor. This is also known as the Nudging model, in which Magnesium activates the channel by pushing the voltage sensor via electrostatic interactions and involves the interactions among side chains in different structural domains. Energy provided by voltage, Ca²⁺, and Mg²⁺ binding will propagate to the activation gate of BK channels to initiate ion conduction through the pore. # Effects on the neuron, organ, body as a whole ## Cellular level BK channels help regulate both the firing of neurons and neurotransmitter release. This modulation of synaptic transmission and electrical discharge at the cellular level is due to BK channel expression in conjunction with other potassium-calcium channels. The opening of these channels causes a drive towards the potassium equilibrium potential and thus play a role in speeding up the repolarization of action potentials. This would effectively allow for more rapid stimulation. There is also a role played in shaping the general repolarization of cells, and thus after hyperpolarization (AHP) of action potentials. The role that BK channels have in the fast phase of AHP has been studied extensively in the hippocampus. It can also play a role in inhibiting the release of neurotransmitters. There are many BK channels in Purkinje cells in the cerebellum, thus highlighting their role in motor coordination and function. Furthermore, BK channels play a role in modulating the activity of dendrites as well as astrocytes and microglia. They not only play a role in the CNS (central nervous system) but also in smooth muscle contractions, the secretion of endocrine cells, and the proliferation of cells. Various γ subunits during early brain development are involved in neuronal excitability and in non-excitable cells they often are responsible as a driving force of calcium. Therefore, these subunits can be targets for therapeutic treatments as BK channel activators. There is further evidence that inhibiting BK channels would prevent the efflux of potassium and thus reduce the usage of ATP, in effect allowing for neuronal survival in low oxygen environments. BK channels can also function as a neuronal protectant in terms such as limiting calcium entry into the cells through methionine oxidation. ## Organ level BK channels also play a role in hearing. This was found when the BK ɑ-subunit was knocked out in mice and progressive loss of cochlear hair cells, and thus hearing loss, was observed. BK channels are not only involved in hearing, but also circadian rhythms. Slo binding proteins (Slobs) can modulate BK channels as a function of circadian rhythms in neurons. BK channels are expressed in the suprachiasmatic nucleus (SCN), which is characterized to influence the pathophysiology of sleep. BK channel openers can also have a protective effect on the cardiovascular system. At a low concentration of calcium BK channels have a greater impact on vascular tone. Furthermore, the signaling system of BK channels in the cardiovascular system have an influence on the functioning of coronary blood flow. One of the functions of the β subunit in the brain includes inhibition of the BK channels, allowing for the slowing of channel properties as well as the ability to aid in prevention of seizures in the temporal lobe. ## Bodily function level Mutations of BK channels, resulting in a lower amount of expression in mRNA, is more common in people who are mentally challenged (via hypofunction ), schizophrenic or autistic. Moreover, increased repolarization caused by BK channel mutations may lead to dependency of alcohol initiation of dyskinesias, epilepsy or paroxysmal movement disorders. Not only are BK channels important in many cellular processes in the adult it also is crucial for proper nutrition supply to a developing fetus. Thus, estrogen can cause an increase in the density of BK channels in the uterus. However, increased expression of BK channels have been found in tumor cells, and this could influence future cancer therapy, discussed more in the pharmacology section. BK channels are ubiquitous throughout the body and thus have a large and vast impact on the body as a whole and at a more cellular level, as discussed. # Pharmacology ## Potential issues Several issues arise when there is a deficit in BK channels. Consequences of the malfunctioning BK channel can affect the functioning of a person in many ways, some more life threatening than others. BK channels can be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide, nitric oxide, and hydrogen sulphide. Mutations in the proteins involved with BK channels or genes encoding BK channels are involved in many diseases. A malfunction of BK channels can proliferate in many disorders such as: epilepsy, cancer, diabetes, asthma, and hypertension. Specifically, β1 defect can increase blood pressure and hydrosaline retention in the kidney. Both loss of function and gain of function mutations have been found to be involved in disorders such as epilepsy and chronic pain. Furthermore, increases in BK channel activation, through gain-of-function mutants and amplification, has links to epilepsy and cancer. Moreover, BK channels play a role in tumors as well as cancers. In certain cancers gBK, a variant ion channel called glioma BK channel, can be found. It is known that BK channels do in some way influence the division of cells during replication, which when unregulated can lead to cancers and tumors. Moreover, an aspect studied includes the migration of cancer cells and the role in which BK channels can facilitate this migration, though much is still unknown. Another reason why BK channel understanding is important involves its role in organ transplant surgery. This is due to the activation of BK channels influencing repolarization of the resting membrane potential. Thus, understanding is crucial for safety in effective transplantation. ## Current developments BK channels can be used as pharmacological targets for the treatment of several medical disorders including stroke and overactive bladder. There have been attempts to develop synthetic molecules targeting BK channels, however their efforts have proven largely ineffective thus far. For instance, BMS-204352, a molecule developed by Bristol-Myers Squibb, failed to improve clinical outcome in stroke patients compared to placebo. However, there have been some success from the agonist to BKCa channels, BMS-204352, in treating deficits observed in Fmr1 knockout mice, a model of Fragile X syndrome. BK channels also function as a blocker in ischemia and are a focus in investigating its use as a therapy for stroke. ## Future directions There are many applications for therapeutic strategies involving BK channels. There has been research displaying that a blockage of BK channels results in an increase in neurotransmitter release, effectively indicating future therapeutic possibilities in cognition enhancement, improved memory, and relieving depression. A behavioral response to alcohol is also modulated by BK channels, therefore further understanding of this relationship can aid treatment in patients who are alcoholics. Oxidative stress on BK channels can lead to the negative impairments of lowering blood pressure through cardiovascular relaxation have on both aging and disease. Thus, the signaling system can be involved in treating hypertension and atherosclerosis through targeting of the ɑ subunit to prevent these detrimental effects. Furthermore, the known role that BK channels can play in cancer and tumors is limited. Thus, there is not a lot of current knowledge regarding specific aspects of BK channels that can influence tumors and cancers. Further study is crucial, as this could lead to immense development in treatments for those suffering from cancer and tumors. It is known that epilepsies are due to over-excitability of neurons, which BK channels have a large impact on controlling hyperexcitability. Therefore, understanding could influence the treatment of epilepsy. Overall, BK channels are a target for future pharmacological agents that can be used for benevolent treatments of disease.	BK channel BK channels (Big Potassium), also known as Maxi-K, slo1, or Kca1.1, are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the cell membrane, hence their name, Big Potassium. These channels can be activated (opened) by either electrical means, or by increasing calcium concentrations in the cell.[1] [2]BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability.[3] BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels. # Structure Structurally, BK channels are homologous to voltage- and ligand-gated potassium channels, having a voltage sensor and pore as the membrane-spanning domain and a cytosolic domain for the binding of intracellular calcium and magnesium.[4] Each monomer of the channel-forming alpha subunit is the product of the KCNMA1 gene (also known as Slo1). The Slo1 subunit has three main structural domains, each with a distinct function: the vvoltage sensing domain (VSD) senses membrane potential across the membrane, the cytosolic domain (senses calcium concentration, Ca²⁺ ions), and the pore-gate domain (PGD) which opens and closes to regulate potassium permeation. The activation gate resides in the PGD, which is located at either the cytosolic side of S6 or the selectivity filter (selectivity is the preference of a channel to conduct a specific ion).[4] The Voltage sensing domain and pore-gated domain are collectively referred as the membrane-spanning domains and are formed by transmembrane segments S1-S4 and S5-S6, respectively. Within the S4 helix contains a series of positively charged residues which serve as the primary voltage sensor.[5] BK channels are quite similar to voltage gated K⁺ channels, however, in BK channels only one positively charged residue (Arg213) is involved in voltage sensing across the membrane.[4] Also unique to BK channels is an additional S0 segment, this segment is required for β subunit modulation.[6][7] and voltage sensitivity.[8] The Cytosolic domain is composed of two RCK (regulator of potassium conductance) domains, RCK1 and RCK2. These domains contain two high affinity Ca²⁺ binding sites: one in the RCK1 domain and the other in a region termed the Ca²⁺ bowl that consists of a series of Aspartic acid (Asp) residues that are located in the RCK2 domain. The Mg²⁺ binding site is located between the VSD and the cytosolic domain, which is formed by: Asp residues within the S0-S1 loop, Asparagine residues in the cytosolic end of S2, and Glutamine residues in RCK1.[4] In forming the Mg²⁺ binding site, two residues come from the RCK1 of one Slo1 subunit and the other two residues come from the VSD of the neighboring subunit. In order for these residues to coordinate the Mg²⁺ ion, the VSD and cytosolic domain from neighboring subunits must be in close proximity.[4] Modulatory beta subunits (encoded by KCNMB1, KCNMB2, KCNMB3, or KCNMB4) can associate with the tetrameric channel. There are four types of β subunits (β1-4), each of which have different expression patterns that modify the gating properties of the BK channel. The β1 subunit is primarily responsible for smooth muscle cell expression, both β2 and β3 subunits are neuronally expressed, while β4 is expressed within the brain.[4] The VSD associates with the PGD via three major interactions: - Physical connection between the VSD and PGD through the S4-S5 linker. - Interactions between the S4-S5 linker and the cytosolic side of S6. - Interactions between S4 and S5 of a neighboring subunit. # Regulation BK channels are associated and modulated by a wide variety of intra- and extracellular factors, such as auxiliary subunits (β, γ), Slobs (slo binding protein), phosphorylation, membrane voltage, chemical ligands (Ca²⁺, Mg²⁺), PKC, The BK α-subunits assemble 1:1 with four different auxiliary types of β-subunits (β1, β2, β3 or β4).[9] Trafficking to and expression of BK channels in the plasma membrane has been found to be regulated by distinct splicing motifs located within the intracellular C-terminal RCK domains. In particular a splice variant that excluded these motifs prevented cell surface expression of BK channels and suggests that such a mechanism impacts physiology and pathophysiology.[9] BK channels in the vascular system are modulated by agents naturally produced in the body, such as angiotensin II (Ang II), high glucose or arachidonic acid (AA) which is modulated in diabetes by oxidative stress (ROS).[9] A weaker voltage sensitivity allows BK channels to function in a wide range of membrane potentials. This ensures that the channel can properly perform its physiological function.[10] Inhibition of BK channel activity by phosphorylation of S695 by protein kinase C (PKC) is dependent on the phosphorylation of S1151 in C terminus of channel alpha-subunit. Only one of these phosphorylations in the tetrameric structure needs to occur for inhibition to be successful. Protein phosphatase 1 counteracts phosphorylation of S695. PKC decreases channel opening probability by shortening the channel open time and prolonging the closed state of the channel. PKC does not affect the single-channel conductance, voltage dependence, or the calcium sensitivity of BK channels.[10] # Activation mechanism BK channels are synergistically activated through the binding of calcium and magnesium ions, but can also be activated via voltage dependence.[9] Ca²⁺ - dependent activation occurs when intracellular Ca²⁺ binds to two high affinity binding sites: one located in the C-terminus of the RCK2 domain (Ca²⁺ bowl), and the other located in the RCK1 domain.[4] The binding site within the RCK1 domain has somewhat of a lower affinity for calcium than the Ca²⁺ bowl, but is responsible for a larger portion of the Ca²⁺ sensitivity.[11] Voltage and calcium activate BK channels using two parallel mechanisms, with the voltage sensors and the Ca²⁺ bindings sites coupling to the activation gate independently, except for a weak interaction between the two mechanisms. The Ca²⁺ bowl accelerates activation kinetics at low Ca²⁺ concentrations while RCK1 site influences both activation and deactivation kinetics.[10] One mechanism model was originally proposed by Monod, Wyman, and Changeux, known as the MWC model. The MWC model for BK channels explains that a conformational change of the activation gate in channel opening is accompanied by a conformational change to the Ca²⁺ binding site, which increases the affinity of Ca²⁺ binding.[11] Magnesium-dependent activation of BK channels activates via a low-affinity metal binding site that is independent from Ca²⁺-dependent activation. The Mg²⁺ sensor activates BK channels by shifting the activation voltage to a more negative range. Mg²⁺ activates the channel only when the voltage sensor domain stays in the activated state. The cytosolic tail domain (CTD) is a chemical sensor that has multiple binding sites for different ligands. The CTD activates the BK channel when bound with intracellular Mg²⁺ to allow for interaction with the voltage sensor domain (VSD).[10] Magnesium is predominantly coordinated by six oxygen atoms from the side chains of oxygen-containing residues, main chain carbonyl groups in proteins, or water molecules.[11] D99 at the C-terminus of the S0-S1 loop and N172 in the S2-S3 loop contain side chain oxygens in the voltage sensor domain that are essential for Mg²⁺ binding. Much like the Ca²⁺-dependent activation model, Mg²⁺-dependent activation can also be described by an allosteric MCW gating model. While calcium activates the channel largely independent of the voltage sensor, magnesium activates the channel by channel by an electrostatic interaction with the voltage sensor.[11] This is also known as the Nudging model, in which Magnesium activates the channel by pushing the voltage sensor via electrostatic interactions and involves the interactions among side chains in different structural domains.[4] Energy provided by voltage, Ca²⁺, and Mg²⁺ binding will propagate to the activation gate of BK channels to initiate ion conduction through the pore.[4] # Effects on the neuron, organ, body as a whole ## Cellular level BK channels help regulate both the firing of neurons and neurotransmitter release.[12] This modulation of synaptic transmission and electrical discharge at the cellular level is due to BK channel expression in conjunction with other potassium-calcium channels.[9] The opening of these channels causes a drive towards the potassium equilibrium potential and thus play a role in speeding up the repolarization of action potentials.[9] This would effectively allow for more rapid stimulation.[9] There is also a role played in shaping the general repolarization of cells, and thus after hyperpolarization (AHP) of action potentials.[13] The role that BK channels have in the fast phase of AHP has been studied extensively in the hippocampus.[13] It can also play a role in inhibiting the release of neurotransmitters.[14] There are many BK channels in Purkinje cells in the cerebellum, thus highlighting their role in motor coordination and function.[13] Furthermore, BK channels play a role in modulating the activity of dendrites as well as astrocytes and microglia.[14] They not only play a role in the CNS (central nervous system) but also in smooth muscle contractions, the secretion of endocrine cells, and the proliferation of cells.[12] Various γ subunits during early brain development are involved in neuronal excitability and in non-excitable cells they often are responsible as a driving force of calcium.[9] Therefore, these subunits can be targets for therapeutic treatments as BK channel activators.[9] There is further evidence that inhibiting BK channels would prevent the efflux of potassium and thus reduce the usage of ATP, in effect allowing for neuronal survival in low oxygen environments.[9] BK channels can also function as a neuronal protectant in terms such as limiting calcium entry into the cells through methionine oxidation.[9] ## Organ level BK channels also play a role in hearing.[13] This was found when the BK ɑ-subunit was knocked out in mice and progressive loss of cochlear hair cells, and thus hearing loss, was observed.[13] BK channels are not only involved in hearing, but also circadian rhythms. Slo binding proteins (Slobs) can modulate BK channels as a function of circadian rhythms in neurons.[9] BK channels are expressed in the suprachiasmatic nucleus (SCN), which is characterized to influence the pathophysiology of sleep.[13] BK channel openers can also have a protective effect on the cardiovascular system.[9] At a low concentration of calcium BK channels have a greater impact on vascular tone.[9] Furthermore, the signaling system of BK channels in the cardiovascular system have an influence on the functioning of coronary blood flow.[9] One of the functions of the β subunit in the brain includes inhibition of the BK channels, allowing for the slowing of channel properties as well as the ability to aid in prevention of seizures in the temporal lobe.[9] ## Bodily function level Mutations of BK channels, resulting in a lower amount of expression in mRNA, is more common in people who are mentally challenged (via hypofunction [14]), schizophrenic or autistic.[9] Moreover, increased repolarization caused by BK channel mutations may lead to dependency of alcohol initiation of dyskinesias, epilepsy or paroxysmal movement disorders.[9] Not only are BK channels important in many cellular processes in the adult it also is crucial for proper nutrition supply to a developing fetus.[9] Thus, estrogen can cause an increase in the density of BK channels in the uterus.[9] However, increased expression of BK channels have been found in tumor cells, and this could influence future cancer therapy, discussed more in the pharmacology section.[9] BK channels are ubiquitous throughout the body and thus have a large and vast impact on the body as a whole and at a more cellular level, as discussed. # Pharmacology ## Potential issues Several issues arise when there is a deficit in BK channels. Consequences of the malfunctioning BK channel can affect the functioning of a person in many ways, some more life threatening than others. BK channels can be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide,[15][16] nitric oxide, and hydrogen sulphide.[17] Mutations in the proteins involved with BK channels or genes encoding BK channels are involved in many diseases. A malfunction of BK channels can proliferate in many disorders such as: epilepsy, cancer, diabetes, asthma, and hypertension.[12] Specifically, β1 defect can increase blood pressure and hydrosaline retention in the kidney.[12] Both loss of function and gain of function mutations have been found to be involved in disorders such as epilepsy and chronic pain.[14] Furthermore, increases in BK channel activation, through gain-of-function mutants and amplification, has links to epilepsy and cancer.[12] Moreover, BK channels play a role in tumors as well as cancers. In certain cancers gBK, a variant ion channel called glioma BK channel, can be found.[13] It is known that BK channels do in some way influence the division of cells during replication, which when unregulated can lead to cancers and tumors.[13] Moreover, an aspect studied includes the migration of cancer cells and the role in which BK channels can facilitate this migration, though much is still unknown.[13] Another reason why BK channel understanding is important involves its role in organ transplant surgery. This is due to the activation of BK channels influencing repolarization of the resting membrane potential.[9] Thus, understanding is crucial for safety in effective transplantation. ## Current developments BK channels can be used as pharmacological targets for the treatment of several medical disorders including stroke[18] and overactive bladder.[19] There have been attempts to develop synthetic molecules targeting BK channels,[20] however their efforts have proven largely ineffective thus far. For instance, BMS-204352, a molecule developed by Bristol-Myers Squibb, failed to improve clinical outcome in stroke patients compared to placebo.[21] However, there have been some success from the agonist to BKCa channels, BMS-204352, in treating deficits observed in Fmr1 knockout mice, a model of Fragile X syndrome.[22] [23] BK channels also function as a blocker in ischemia and are a focus in investigating its use as a therapy for stroke.[9] ## Future directions There are many applications for therapeutic strategies involving BK channels. There has been research displaying that a blockage of BK channels results in an increase in neurotransmitter release, effectively indicating future therapeutic possibilities in cognition enhancement, improved memory, and relieving depression.[12] A behavioral response to alcohol is also modulated by BK channels,[9] therefore further understanding of this relationship can aid treatment in patients who are alcoholics. Oxidative stress on BK channels can lead to the negative impairments of lowering blood pressure through cardiovascular relaxation have on both aging and disease.[9] Thus, the signaling system can be involved in treating hypertension and atherosclerosis[9] through targeting of the ɑ subunit to prevent these detrimental effects. Furthermore, the known role that BK channels can play in cancer and tumors is limited. Thus, there is not a lot of current knowledge regarding specific aspects of BK channels that can influence tumors and cancers.[13] Further study is crucial, as this could lead to immense development in treatments for those suffering from cancer and tumors. It is known that epilepsies are due to over-excitability of neurons, which BK channels have a large impact on controlling hyperexcitability.[3] Therefore, understanding could influence the treatment of epilepsy. Overall, BK channels are a target for future pharmacological agents that can be used for benevolent treatments of disease.	https://www.wikidoc.org/index.php/BK_channel
36aee4498e05fdef08a115f40a1be0eb50969882	wikidoc	BMF (gene)	BMF (gene) Bcl-2-modifying factor is a protein that in humans is encoded by the BMF gene. The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein contains a single BCL2 homology domain 3 (BH3), and has been shown to bind BCL2 proteins and function as an apoptotic activator. This protein is found to be sequestered to myosin V motors by its association with dynein light chain 2, which may be important for sensing intracellular damage and triggering apoptosis. Alternatively spliced transcript variants encoding different isoforms have been identified. # Interactions BMF (gene) has been shown to interact with Bcl-2 and DYNLL2.	BMF (gene) Bcl-2-modifying factor is a protein that in humans is encoded by the BMF gene.[1][2] The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein contains a single BCL2 homology domain 3 (BH3), and has been shown to bind BCL2 proteins and function as an apoptotic activator. This protein is found to be sequestered to myosin V motors by its association with dynein light chain 2, which may be important for sensing intracellular damage and triggering apoptosis. Alternatively spliced transcript variants encoding different isoforms have been identified.[2] # Interactions BMF (gene) has been shown to interact with Bcl-2[1] and DYNLL2.[1][3]	https://www.wikidoc.org/index.php/BMF_(gene)
7cad8371678d9456288196029f6c3d2fb043854a	wikidoc	BOK (gene)	BOK (gene) Bok (Bcl-2 related ovarian killer) is a protein-coding gene of the Bcl-2 family that is found in many invertebrates and vertebrates. It induces apoptosis, a special type of cell death. Currently, the precise function of Bok in this process is unknown. # Discovery and homology In 1997, the protein Bcl-2-related ovarian killer (Bok) was identified in a yeast two-hybrid experiment with a rat ovarian cDNA library in a screen for proteins interacting with Mcl-1, an abundant anti-apoptotic protein. The overexpression of Bok induces apoptosis. Because of its high sequence similarity to Bak and Bax, Bok is classified as a member of the Bcl-2 protein family. The mouse homologue of Bok is called Matador (Mtd). This name is derived from the Latin term mactator which means butcher or killer. Additionally, homologous proteins were found in Drosophila melanogaster (fruit fly) and Gallus gallus (chicken). # Promoter and gene structure The human BOK promoter is activated by the overexpression of members of the E2F hand transcription factor family. Typically, these transcription factors are involved in the promotion of S-phase, so there might be a connection between Bok expression and cell cycle progression. Due to this regulation of Bok expression by the cell cycle, it was proposed that Bok sensitizes growing cells to stress-induced apoptosis. Bok mRNA comprises five exons which code for a 213 amino acid protein, called Bok-L. This protein consists of four Bcl-2 homology domains (abbreviated BH1, BH2, BH3, BH4, respectively) and a C-terminal transmembrane region (Figure 1). Its BH3 domain contains a stretch with many leucine residues. This is unique among the Bcl-2 family members. The leucine-rich stretch functions as a nuclear export signal. It is recognized by the nuclear exportin Crm1. Mutations in the leucine-rich stretch impair the binding of Crm1 to Bok. Consequently, Bok accumulates in the nucleus and triggers apoptosis. # Splice variants Due to alternative splicing, Bok mRNA gives rise to different Bok proteins: Figure 1 illustrates the different splice variants schematically. Full length Bok is named Bok-L. The shorter version, Bok-S, lacks exon 3. This results in a fusion of the BH3 domain with the BH1 domain. The BH3 domain is involved in the interaction of Bok with Mcl-1 and other molecules. It is dispensable for the induction of apoptosis. Expression of Bok-S may be an immediate response to stress signals. It has been shown to induce apoptosis regardless of the presence of anti-apoptotic molecules. Another splice variant termed Bok-P was found in placental tissue from patients suffering from pre-eclampsia. While Bok-S misses exon 3, Bok-P lacks exon 2. This deletion includes the BH4 domain and parts of the BH3 domain. Bok-P may be the cause for trophoblast cell death in pre-eclampsia, a dangerous pregnancy complication. In pre-eclampsia, typical alterations occur in the maternal kidney and lead to hypertension and proteins in the urine. To date, the cause of this medical condition as well as an appropriate treatment have not been discovered. # Expression pattern The Bok gene is activated and produces protein in different tissues. In mice, elevated Bok levels were detected in the ovary, the testis, and the uterus. Nevertheless, it also exists in the brain and at low levels in most other tissues. However, the expression pattern of the Bok gene varies among species. In humans, Bok is found in a wide range of tissues. The gene is expressed in the colon, the stomach, the testes, the placenta, the pancreas, the ovaries, and the uterus. Furthermore, more Bok is expressed in fetal tissue compared to adult tissue. Thus, Bok may influence development. # Subcellular localization The subcellular localization of Bok protein is controversial. In proliferating cells, Bok is found in the nucleus. Upon induction of apoptosis, it was found to tightly associate with mitochondrial membranes. On the other hand, another group found Bok shuttling between the cytoplasm and the nucleus. In their experiments, increased nuclear (not mitochondrial) localization correlated with a stronger apoptotic activity. # Regulation It was found that the cellular ratio of pro-apoptotic to anti-apoptotic Bcl-2 family members effects late apoptotic events such as release of cytochrome c from the mitochondria and the activation of caspases. Higher levels of pro-apoptotic proteins compared to anti-apoptotic proteins seem to cause apoptosis. In a current model, the formation of heterodimers between pro-apoptotic and anti-apoptotic proteins prevents induction of apoptosis. # Interactions The binding of Bok to its interacting partners seems to be mediated by its BH3 domain. The splice variant Bok-S lacks this domain and is unable to form heterodimers with other proteins of the Bcl-2 family. In yeast two-hybrid experiments, Bok was found to interact with the anti-apoptotic proteins Mcl-1, BHRF-1, and Bfl-1. However, interactions with other anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w were not detectable (1). Later studies aimed at confirming an interaction between Bok and pro-apoptotic Bak or Bax but were not successful. Accordingly, coexpression of anti-apoptotic proteins such as Mcl-1 suppresses apoptosis induced by Bok overexpression. Consistent with the results mentioned above, coexpression of anti-apoptotic Bcl-2 does not prevent Bok-induced apoptosis. # Knock-out mouse Since its discovery in 1997, several attempts have been made to characterize Bok. Due to the increased expression levels in fetal tissue, scientists anticipated a developmental role for Bok. Recently, the Bok knock-out mouse was created. This mouse shows, however, no developmental defects and normal fertility. This finding indicates that the function of Bok seems to overlap with the function of the related pro-apoptotic proteins Bak and Bax. Several other roles were proposed for Bok, especially in developing cells. Since the action of Bok in triggering apoptosis seems to be redundant, it is difficult to assign a specific role to Bok in the presence of Bak and Bax. The study of cells deficient in Bak and Bok or deficient in Bax and Bok, respectively, could help to better characterize the role of Bok in apoptosis. If Bok exerts a critical function, it is likely that this function is limited to certain circumstances, e.g. specific cell types, stress conditions. Thus, these aspects should be assessed in more detail to analyze the physiological and pathological role of Bok.	BOK (gene) Bok (Bcl-2 related ovarian killer) is a protein-coding gene of the Bcl-2 family that is found in many invertebrates and vertebrates. It induces apoptosis, a special type of cell death. Currently, the precise function of Bok in this process is unknown. # Discovery and homology In 1997, the protein Bcl-2-related ovarian killer (Bok) was identified in a yeast two-hybrid experiment with a rat ovarian cDNA library in a screen for proteins interacting with Mcl-1, an abundant anti-apoptotic protein.[1] The overexpression of Bok induces apoptosis. Because of its high sequence similarity to Bak and Bax,[2] Bok is classified as a member of the Bcl-2 protein family.[3] The mouse homologue of Bok is called Matador (Mtd). This name is derived from the Latin term mactator which means butcher or killer.[4] Additionally, homologous proteins were found in Drosophila melanogaster (fruit fly) and Gallus gallus (chicken).[5] # Promoter and gene structure The human BOK promoter is activated by the overexpression of members of the E2F hand transcription factor family. Typically, these transcription factors are involved in the promotion of S-phase, so there might be a connection between Bok expression and cell cycle progression.[6] Due to this regulation of Bok expression by the cell cycle, it was proposed that Bok sensitizes growing cells to stress-induced apoptosis.[6] Bok mRNA comprises five exons which code for a 213 amino acid protein,[3] called Bok-L. This protein consists of four Bcl-2 homology domains (abbreviated BH1, BH2, BH3, BH4, respectively) and a C-terminal transmembrane region [3] (Figure 1). Its BH3 domain contains a stretch with many leucine residues. This is unique among the Bcl-2 family members. The leucine-rich stretch functions as a nuclear export signal.[7] It is recognized by the nuclear exportin Crm1. Mutations in the leucine-rich stretch impair the binding of Crm1 to Bok.[7] Consequently, Bok accumulates in the nucleus and triggers apoptosis.[7] # Splice variants Due to alternative splicing, Bok mRNA gives rise to different Bok proteins: Figure 1 illustrates the different splice variants schematically. Full length Bok is named Bok-L. The shorter version, Bok-S, lacks exon 3. This results in a fusion of the BH3 domain with the BH1 domain.[2][8] The BH3 domain is involved in the interaction of Bok with Mcl-1 and other molecules. It is dispensable for the induction of apoptosis.[8] Expression of Bok-S may be an immediate response to stress signals. It has been shown to induce apoptosis regardless of the presence of anti-apoptotic molecules.[2] Another splice variant termed Bok-P was found in placental tissue from patients suffering from pre-eclampsia. While Bok-S misses exon 3, Bok-P lacks exon 2. This deletion includes the BH4 domain and parts of the BH3 domain. Bok-P may be the cause for trophoblast cell death in pre-eclampsia,[3] a dangerous pregnancy complication. In pre-eclampsia, typical alterations occur in the maternal kidney and lead to hypertension and proteins in the urine. To date, the cause of this medical condition as well as an appropriate treatment have not been discovered. # Expression pattern The Bok gene is activated and produces protein in different tissues. In mice, elevated Bok levels were detected in the ovary, the testis, and the uterus.[1] Nevertheless, it also exists in the brain and at low levels in most other tissues.[9] However, the expression pattern of the Bok gene varies among species. In humans, Bok is found in a wide range of tissues. The gene is expressed in the colon, the stomach, the testes, the placenta, the pancreas, the ovaries, and the uterus.[10] Furthermore, more Bok is expressed in fetal tissue compared to adult tissue. Thus, Bok may influence development. # Subcellular localization The subcellular localization of Bok protein is controversial. In proliferating cells, Bok is found in the nucleus.[11] Upon induction of apoptosis, it was found to tightly associate with mitochondrial membranes.[10][11] On the other hand, another group found Bok shuttling between the cytoplasm and the nucleus. In their experiments, increased nuclear (not mitochondrial) localization correlated with a stronger apoptotic activity.[7] # Regulation It was found that the cellular ratio of pro-apoptotic to anti-apoptotic Bcl-2 family members effects late apoptotic events such as release of cytochrome c from the mitochondria and the activation of caspases. Higher levels of pro-apoptotic proteins compared to anti-apoptotic proteins seem to cause apoptosis. In a current model, the formation of heterodimers between pro-apoptotic and anti-apoptotic proteins prevents induction of apoptosis.[8] # Interactions The binding of Bok to its interacting partners seems to be mediated by its BH3 domain.[3] The splice variant Bok-S lacks this domain and is unable to form heterodimers with other proteins of the Bcl-2 family. In yeast two-hybrid experiments, Bok was found to interact with the anti-apoptotic proteins Mcl-1, BHRF-1, and Bfl-1. However, interactions with other anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w were not detectable (1). Later studies aimed at confirming an interaction between Bok and pro-apoptotic Bak or Bax but were not successful.[4] Accordingly, coexpression of anti-apoptotic proteins such as Mcl-1 suppresses apoptosis induced by Bok overexpression.[1] Consistent with the results mentioned above, coexpression of anti-apoptotic Bcl-2 does not prevent Bok-induced apoptosis.[1] # Knock-out mouse Since its discovery in 1997, several attempts have been made to characterize Bok. Due to the increased expression levels in fetal tissue, scientists anticipated a developmental role for Bok. Recently, the Bok knock-out mouse was created. This mouse shows, however, no developmental defects and normal fertility.[9] This finding indicates that the function of Bok seems to overlap with the function of the related pro-apoptotic proteins Bak and Bax. Several other roles were proposed for Bok, especially in developing cells.[8][12][13][14] Since the action of Bok in triggering apoptosis seems to be redundant, it is difficult to assign a specific role to Bok in the presence of Bak and Bax. The study of cells deficient in Bak and Bok or deficient in Bax and Bok, respectively, could help to better characterize the role of Bok in apoptosis. If Bok exerts a critical function, it is likely that this function is limited to certain circumstances, e.g. specific cell types, stress conditions. Thus, these aspects should be assessed in more detail to analyze the physiological and pathological role of Bok.	https://www.wikidoc.org/index.php/BOK_(gene)
00789c0103c4a5580079de7b2820c833fa2a7078	wikidoc	B symptoms	B symptoms # Overview B symptoms refer to systemic symptoms of fever, night sweats, and weight loss which can be associated with both Hodgkin's lymphoma and non-Hodgkin's lymphoma. The presence or absence of B symptoms has prognostic significance and is reflected in the staging of these lymphomas. # Description and nomenclature B symptoms are so called because lymphoma staging includes both a number (I-IV) and a letter (A or B). "A" indicates the absence of systemic symptoms, while "B" indicates their presence. B symptoms include: - Fever greater than 38°C. Pel-Ebstein fever, the classic intermittent fever associated with Hodgkin disease, occurs at variable intervals of days to weeks and lasts for 1-2 weeks before resolving. However, fever associated with lymphoma can follow virtually any pattern. - Drenching sweats, especially at night. - Unintentional weight loss of >10% of normal body weight over a period of 6 months or less. # Prognostic importance The presence of B symptoms is a marker for more advanced disease with systemic, rather than merely local, involvement. B symptoms are a clear negative prognostic factor in Hodgkin lymphoma. The relevance of B symptoms in non-Hodgkin lymphoma is less clear, although here also B symptoms tend to correlate with disease that is either more widespread or of a higher histologic grade. ## Relative importance of specific B symptoms It has been suggested that, in Hodgkin lymphoma, fever and weight loss are much more prognostically significant than night sweats. In one series of patients with early-stage Hodgkin disease, the presence or absence of night sweats had no impact on cure rates and outcome. However, fever and weight loss had a pronounced negative impact on cure and survival rates, regardless of treatment modality. # "B symptoms" in other diseases Similar systemic symptoms can be found in non-cancerous states such as tuberculosis and various inflammatory or rheumatologic conditions. In these settings, the term "B symptoms" is sometimes colloquially applied to refer to such systemic or constitutional symptoms. However, in a pure sense, the term "B symptoms" is restricted to lymphoma staging.	B symptoms Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview B symptoms refer to systemic symptoms of fever, night sweats, and weight loss which can be associated with both Hodgkin's lymphoma and non-Hodgkin's lymphoma. The presence or absence of B symptoms has prognostic significance and is reflected in the staging of these lymphomas. # Description and nomenclature B symptoms are so called because lymphoma staging includes both a number (I-IV) and a letter (A or B). "A" indicates the absence of systemic symptoms, while "B" indicates their presence. B symptoms include: - Fever greater than 38°C. Pel-Ebstein fever, the classic intermittent fever associated with Hodgkin disease, occurs at variable intervals of days to weeks and lasts for 1-2 weeks before resolving. However, fever associated with lymphoma can follow virtually any pattern. - Drenching sweats, especially at night. - Unintentional weight loss of >10% of normal body weight over a period of 6 months or less. # Prognostic importance The presence of B symptoms is a marker for more advanced disease with systemic, rather than merely local, involvement. B symptoms are a clear negative prognostic factor in Hodgkin lymphoma.[1] The relevance of B symptoms in non-Hodgkin lymphoma is less clear, although here also B symptoms tend to correlate with disease that is either more widespread or of a higher histologic grade.[2] ## Relative importance of specific B symptoms It has been suggested that, in Hodgkin lymphoma, fever and weight loss are much more prognostically significant than night sweats. In one series of patients with early-stage Hodgkin disease, the presence or absence of night sweats had no impact on cure rates and outcome. However, fever and weight loss had a pronounced negative impact on cure and survival rates, regardless of treatment modality.[3] # "B symptoms" in other diseases Similar systemic symptoms can be found in non-cancerous states such as tuberculosis and various inflammatory or rheumatologic conditions. In these settings, the term "B symptoms" is sometimes colloquially applied to refer to such systemic or constitutional symptoms. However, in a pure sense, the term "B symptoms" is restricted to lymphoma staging.	https://www.wikidoc.org/index.php/B_symptoms
41c6c81f1e8e8c72441fc96d52adbead43fde842	wikidoc	Human back	Human back The human back is the large posterior area of the human body, rising from the top of the buttocks to the back of the neck and the shoulders. It is the surface opposite to the chest, its height being defined by the vertebral column (commonly referred to as the spine or backbone) and its breadth being supported by the ribcage and shoulders. The spinal canal runs through the spine and provides nerves to the rest of the body. # Anatomy of the back ## Skeletal structure of the back The central feature of the human back is the vertebral column, specifically the length from the top of the thoracic vertebrae to the bottom of the lumbar vertebrae, which houses the spinal cord in its spinal canal, and which generally has some curvature that gives shape to the back. The ribcage extends from the spine at the top of the back (with the top of the ribcage corresponding to the T1 vertebra), more than halfway down the length of the back, leaving an area with less protection between the bottom of the ribcage and the hips. The width of the back at the top is defined by the scapula, the broad, flat bones of the shoulders. ## Muscles of the back The spine is bordered by several groups of muscles, including the intertransversarii muscle which facilitate movement between the individual vertabrae, and the multifidus spinae, which facilitate the movement of the spine as a whole. Other muscles in the back are associated with the movement of the neck and shoulders. The trapezius muscle, which is named from its trapezium-like shape, runs between the neck, the anterior chain, the two shoulders, and the thoracic vertebra, T12. The large latissimus dorsi make a triangle from the shoulder to the hip. The significant mass of muscles in the back can be developed through back exercises. ## Function of the back The intricate anatomy of the back is designed to both provide support for the head and trunk of the body, strength in the trunk of the body, as well as a great deal of flexibility and movement. The upper back has the most structural support, with the ribs attached firmly to each level of the thoracic spine and very limited movement. The lower back allows for flexibility and movement in all directions. ## Back pain The back comprises interconnecting nerves, bones, muscles, ligaments and tendons, all of which can be a source of pain. Back pain is one of the most common types of pain in adults. By far the most common cause of back pain is muscle strain. The back muscles can usually heal themselves within a couple of weeks, but the pain can be intense and debilitating. Other common sources of back pain include disc problems, such as degenerative disc disease or a lumbar disc herniation, many types of fractures, such as spondylolisthesis or an osteoporotic fracture, or osteoarthritis . ## Organs of the back The lungs are within the ribcage, and extend to the back of the ribcage, making it possible for them to be listened into through the back. The kidneys are situated beneath the muscles in the area below the end of the ribcage, loosely connected to the peritoneum. A strike to the lower back can damage the kidneys of the person being hit. ## Surface of the back The skin of the human back is thicker and has fewer nerve endings than the skin on any other part of the torso. With some notable exceptions (see, e.g. George "The Animal" Steele), it tends to have less hair than the chest on men. The upper-middle back is also the one area of the body which a typical human under normal conditions might be unable to physically touch. When this area is itchy, a backscratcher can be used to ease the discomfort. # Significance in human society The curvature of the female back is a frequent theme in paintings, because the sensibilities of many cultures permit the back to be shown nude - implying full nudity without actually displaying it. Indeed, the practice of showing explicitness on the lower back has been performed for centuries. Certain articles of clothing, such as the haltertop and the backless dress, are designed to expose the back in this manner. The back also serves as the largest canvas for body art on the human body. Because of its size and the relative lack of hair, the back presents an ideal canvas on the human body for Lower back tattoos. Indeed, some individuals have tattoos that cover the entirety of the back. Others have smaller tattoos at significant locations, such as the shoulder blade or the bottom of the back. Many English idioms mention the back, usually highlighting it as an area of vulnerability; one must "watch one's back", or one may end up "with one's back up against the wall"; worse yet, someone may "stab one in the back", but hopefully a friend "has got one's back". The back is also a symbol of strength and hard work, with those seeking physical labor looking for "strong backs", and workers being implored to "put their back into it".	Human back Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The human back is the large posterior area of the human body, rising from the top of the buttocks to the back of the neck and the shoulders. It is the surface opposite to the chest, its height being defined by the vertebral column (commonly referred to as the spine or backbone) and its breadth being supported by the ribcage and shoulders. The spinal canal runs through the spine and provides nerves to the rest of the body. # Anatomy of the back ## Skeletal structure of the back The central feature of the human back is the vertebral column, specifically the length from the top of the thoracic vertebrae to the bottom of the lumbar vertebrae, which houses the spinal cord in its spinal canal, and which generally has some curvature that gives shape to the back. The ribcage extends from the spine at the top of the back (with the top of the ribcage corresponding to the T1 vertebra), more than halfway down the length of the back, leaving an area with less protection between the bottom of the ribcage and the hips. The width of the back at the top is defined by the scapula, the broad, flat bones of the shoulders. ## Muscles of the back The spine is bordered by several groups of muscles, including the intertransversarii muscle which facilitate movement between the individual vertabrae, and the multifidus spinae, which facilitate the movement of the spine as a whole. Other muscles in the back are associated with the movement of the neck and shoulders. The trapezius muscle, which is named from its trapezium-like shape, runs between the neck, the anterior chain, the two shoulders, and the thoracic vertebra, T12. The large latissimus dorsi make a triangle from the shoulder to the hip. The significant mass of muscles in the back can be developed through back exercises. ## Function of the back The intricate anatomy of the back is designed to both provide support for the head and trunk of the body, strength in the trunk of the body, as well as a great deal of flexibility and movement. The upper back has the most structural support, with the ribs attached firmly to each level of the thoracic spine and very limited movement. The lower back allows for flexibility and movement in all directions. ## Back pain The back comprises interconnecting nerves, bones, muscles, ligaments and tendons, all of which can be a source of pain. Back pain is one of the most common types of pain in adults. By far the most common cause of back pain is muscle strain. The back muscles can usually heal themselves within a couple of weeks, but the pain can be intense and debilitating. Other common sources of back pain include disc problems, such as degenerative disc disease or a lumbar disc herniation, many types of fractures, such as spondylolisthesis or an osteoporotic fracture, or osteoarthritis [2]. ## Organs of the back The lungs are within the ribcage, and extend to the back of the ribcage, making it possible for them to be listened into through the back. The kidneys are situated beneath the muscles in the area below the end of the ribcage, loosely connected to the peritoneum. A strike to the lower back can damage the kidneys of the person being hit. ## Surface of the back The skin of the human back is thicker and has fewer nerve endings than the skin on any other part of the torso. With some notable exceptions (see, e.g. George "The Animal" Steele), it tends to have less hair than the chest on men. The upper-middle back is also the one area of the body which a typical human under normal conditions might be unable to physically touch. When this area is itchy, a backscratcher can be used to ease the discomfort. # Significance in human society The curvature of the female back is a frequent theme in paintings, because the sensibilities of many cultures permit the back to be shown nude - implying full nudity without actually displaying it. Indeed, the practice of showing explicitness on the lower back has been performed for centuries. Certain articles of clothing, such as the haltertop and the backless dress, are designed to expose the back in this manner. The back also serves as the largest canvas for body art on the human body. Because of its size and the relative lack of hair, the back presents an ideal canvas on the human body for Lower back tattoos. Indeed, some individuals have tattoos that cover the entirety of the back. Others have smaller tattoos at significant locations, such as the shoulder blade or the bottom of the back. Many English idioms mention the back, usually highlighting it as an area of vulnerability; one must "watch one's back", or one may end up "with one's back up against the wall"; worse yet, someone may "stab one in the back", but hopefully a friend "has got one's back". The back is also a symbol of strength and hard work, with those seeking physical labor looking for "strong backs", and workers being implored to "put their back into it".	https://www.wikidoc.org/index.php/Back
60058f89127148830b1024aabf4a43a55d9e7b4e	wikidoc	Back brace	Back brace # Overview A back brace is a device designed to limit the motion of the spine in cases of fracture or in post-operative fusions. Limiting the motion of the spine enhances the healing process and minimizes the patient's discomfort. Common brack braces include: - Rigid braces : These braces are form-fitting plastic molds that restrict motion by as much as 50%; and - Corset braces : Elastic braces that limit forward motion of the spine and assist in setting spinal fusions or supporting the spine during occasions of stress (for example, employment requiring the lifting of heavy loads). # Bracing for scoliosis Back braces are also commonly prescribed to treat adolescent idiopathic scoliosis, as they may stop the progression of spinal curvature in a growing child. There are several types of back braces commonly used to treat adolescent idiopathic scoliosis. Each of these braces is a rigid brace that works by putting pressure on an existing curvature to prevent its progression. Some of these devices are custom measured or cast by an orthotist or within a clinical team. Normally some type of protective layer, such as a tank top or white T-shirt, are worn underneath the brace to prevent blistering and skin burns. - The most commonly used brace is the Boston, made of molded plastic and generally worn under clothing. The brace can be removed for sport activities but is typically worn at all other times. - The Cervico-Thoraco-Lumbo-Sacral Orthosis brace (also known as a Milwaukee brace) is similar to the Boston brace in construction and use. It includes a neck ring attached to the body of the brace to support the cervical spine. - The Charleston brace is worn while sleeping. This brace is typically molded to a patient bent to the side, which increases the pressure on the curvature. Studies have shown that the Charleston nighttime brace is as effective in 8 hours as the others are in 23 hours. To be effective, the existing curvature must be in the 20 to 40 degree range and the apex of the curve needs to be below the level of the shoulder blade. - The SpineCor brace is worn 20 hours a day. This brace is flexible and allows freedom of movement, and is less noticeable under clothing. Wearing a bodysuit is recommended. Treatment range of the brace is the Cobb angle of between 15 and 50 degrees. The brace is a new design, but a study showed positive results in a two-year follow up. The brace is not meant for patients with a Risser above 3. - The SPoRT is a solid brace with large weeping pads("drives") to facilitate elongation, and "stops" to prevent the patient from moving incorrectly in relation to the curve. A principal advantage of this brace is that it does not limit limb movement. It is usually worn 23 hours a day. - The Cheneau brace is used mostly with the Schroth Method of scoliosis rehabiliation. The "shell" is padded with large, sweeping pads, and there are spaces that are "bumped" out for patient movement. A modified version, the "Lite Cheneau" has spaces instead of the "bumped" sections.	Back brace # Overview A back brace is a device designed to limit the motion of the spine in cases of fracture or in post-operative fusions. Limiting the motion of the spine enhances the healing process and minimizes the patient's discomfort. Common brack braces include: - Rigid braces : These braces are form-fitting plastic molds that restrict motion by as much as 50%; and - Corset braces : Elastic braces that limit forward motion of the spine and assist in setting spinal fusions or supporting the spine during occasions of stress (for example, employment requiring the lifting of heavy loads). # Bracing for scoliosis Back braces are also commonly prescribed to treat adolescent idiopathic scoliosis, as they may stop the progression of spinal curvature in a growing child. There are several types of back braces commonly used to treat adolescent idiopathic scoliosis. Each of these braces is a rigid brace that works by putting pressure on an existing curvature to prevent its progression. Some of these devices are custom measured or cast by an orthotist or within a clinical team. Normally some type of protective layer, such as a tank top or white T-shirt, are worn underneath the brace to prevent blistering and skin burns. - The most commonly used brace is the Boston, made of molded plastic and generally worn under clothing. The brace can be removed for sport activities but is typically worn at all other times. - The Cervico-Thoraco-Lumbo-Sacral Orthosis brace (also known as a Milwaukee brace) is similar to the Boston brace in construction and use. It includes a neck ring attached to the body of the brace to support the cervical spine. - The Charleston brace is worn while sleeping. This brace is typically molded to a patient bent to the side, which increases the pressure on the curvature. Studies have shown that the Charleston nighttime brace is as effective in 8 hours as the others are in 23 hours[citation needed]. To be effective, the existing curvature must be in the 20 to 40 degree range and the apex of the curve needs to be below the level of the shoulder blade. - The SpineCor brace is worn 20 hours a day. This brace is flexible and allows freedom of movement, and is less noticeable under clothing. Wearing a bodysuit is recommended. Treatment range of the brace is the Cobb angle of between 15 and 50 degrees. The brace is a new design, but a study showed positive results in a two-year follow up. The brace is not meant for patients with a Risser above 3. - The SPoRT is a solid brace with large weeping pads("drives") to facilitate elongation, and "stops" to prevent the patient from moving incorrectly in relation to the curve. A principal advantage of this brace is that it does not limit limb movement. It is usually worn 23 hours a day. - The Cheneau brace is used mostly with the Schroth Method of scoliosis rehabiliation. The "shell" is padded with large, sweeping pads, and there are spaces that are "bumped" out for patient movement. A modified version, the "Lite Cheneau" has spaces instead of the "bumped" sections.	https://www.wikidoc.org/index.php/Back_brace
2e360cbefec69ef3f02b43db2c439a1415b1b6b2	wikidoc	Bacteremia	Bacteremia Bacteremia (Bacteræmia in British English, also known as blood poisoning or toxemia) is the presence of bacteria in the blood. Bacteremia is different to sepsis in that it refers to the presence, not the replication, of pathogens. # Diagnosis Bacteremia is most commonly diagnosed by blood culture, in which a sample of blood is allowed to incubate with a medium that promotes bacterial growth. Since blood is normally sterile, this process does not normally lead to the isolation of bacteria. If, however, bacteria are present in the bloodstream at the time the sample is obtained, the bacteria will multiply and can thereby be detected. Any bacteria that incidentally find their way to the culture medium will also multiply. For this reason, blood cultures must be drawn with great attention to sterile process. Occasionally, blood cultures will reveal the presence of bacteria that represent contamination from the skin through which the culture was obtained. Blood cultures must be repeated at intervals to determine if persistent — rather than transient — bacteremia is present. ## Excluding endocarditis A clinical prediction rule aids in identifying patients with bacteremia from staphylococcus aureus who might develop bacterial endocarditis. # Causes - In the hospital, indwelling catheters are a frequent cause of bacteremia and subsequent nosocomial infections, because they provide a means by which bacteria normally found on the skin can enter the bloodstream. Other causes of bacteremia include dental procedures (occasionally including simple tooth brushing), herpes (including herpetic whitlow), urinary tract infections, intravenous drug use, and colorectal cancer. - Bacteremia may also be seen in oropharyngeal, gastrointestinal or genitourinary surgery or exploration. - Drugs: caspofungin acetate, Indinavir # Consequences Bacteremia is the principal means by which local infections are spread to distant organs (referred to as hematogenous spread). Bacteremia is typically transient rather than continuous, due to a vigorous immune system response when bacteria are detected in the blood. Hematogenous dissemination of bacteria is part of the pathophysiology of meningitis, endocarditis, aortitis, Pott's disease and many other forms of osteomyelitis. A related condition, septicemia, refers to the presence of bacteria or their toxins in the bloodstream. Bacteremia, as noted above, frequently elicits a vigorous immune system response. The constellation of findings related to this response (such as fever, chills, or hypotension) is referred to as sepsis. In the setting of more severe disturbances of temperature, respiration, heart rate or white blood cell count, the response is characterized as sepsis syndrome, septic shock, and may result in multiple organ dysfunction syndrome. # Follow-up In some settings, blood cultures should be repeated to verify cure: - Original infection was gram positive cocci including enterococci - Central venous catheter or endovascular source presence - Hemodialysis - Persistent fever Follow-up blood cultures may be positive with the same pathogen in 7% to 10% to 14% of patients. If repeat blood cultures are obtained in the initial 72 hours of antibiotics, a higher rate of 46% are positive. Repeating blood cultures among patients with intravenous catheters may require special methods.	Bacteremia Bacteremia (Bacteræmia in British English, also known as blood poisoning or toxemia) is the presence of bacteria in the blood. Bacteremia is different to sepsis in that it refers to the presence, not the replication, of pathogens. # Diagnosis Bacteremia is most commonly diagnosed by blood culture, in which a sample of blood is allowed to incubate with a medium that promotes bacterial growth. Since blood is normally sterile, this process does not normally lead to the isolation of bacteria. If, however, bacteria are present in the bloodstream at the time the sample is obtained, the bacteria will multiply and can thereby be detected. Any bacteria that incidentally find their way to the culture medium will also multiply. For this reason, blood cultures must be drawn with great attention to sterile process. Occasionally, blood cultures will reveal the presence of bacteria that represent contamination from the skin through which the culture was obtained. Blood cultures must be repeated at intervals to determine if persistent — rather than transient — bacteremia is present. ## Excluding endocarditis A clinical prediction rule aids in identifying patients with bacteremia from staphylococcus aureus who might develop bacterial endocarditis.[1] # Causes - In the hospital, indwelling catheters are a frequent cause of bacteremia and subsequent nosocomial infections, because they provide a means by which bacteria normally found on the skin can enter the bloodstream. Other causes of bacteremia include dental procedures (occasionally including simple tooth brushing), herpes (including herpetic whitlow), urinary tract infections, intravenous drug use, and colorectal cancer. - Bacteremia may also be seen in oropharyngeal, gastrointestinal or genitourinary surgery or exploration. - Drugs: caspofungin acetate, Indinavir # Consequences Bacteremia is the principal means by which local infections are spread to distant organs (referred to as hematogenous spread). Bacteremia is typically transient rather than continuous, due to a vigorous immune system response when bacteria are detected in the blood. Hematogenous dissemination of bacteria is part of the pathophysiology of meningitis, endocarditis, aortitis, Pott's disease and many other forms of osteomyelitis. A related condition, septicemia, refers to the presence of bacteria or their toxins in the bloodstream. Bacteremia, as noted above, frequently elicits a vigorous immune system response. The constellation of findings related to this response (such as fever, chills, or hypotension) is referred to as sepsis. In the setting of more severe disturbances of temperature, respiration, heart rate or white blood cell count, the response is characterized as sepsis syndrome, septic shock, and may result in multiple organ dysfunction syndrome. # Follow-up In some settings, blood cultures should be repeated to verify cure[2][3][4]: - Original infection was gram positive cocci[2][3] including enterococci[5] - Central venous catheter[2] or endovascular source[3] presence - Hemodialysis[2] - Persistent fever[2] Follow-up blood cultures may be positive with the same pathogen in 7%[3] to 10%[4] to 14%[2] of patients. If repeat blood cultures are obtained in the initial 72 hours of antibiotics, a higher rate of 46% are positive[6]. Repeating blood cultures among patients with intravenous catheters may require special methods[7].	https://www.wikidoc.org/index.php/Bacteraemia
8aa2f02849f1aa3add0cd2f6aa6b4f032596043e	wikidoc	Balsam Fir	Balsam Fir The Balsam Fir (Abies balsamea) is a North American fir, native to most of eastern and central Canada (Newfoundland west to central Alberta) and the northeastern United States (Minnesota east to Maine, and south in the Appalachian Mountains to West Virginia). It is a small to medium-size evergreen tree typically 14-20 m tall, rarely to 27 m tall, with a narrow conic crown. The bark on young trees is smooth, grey, and with resin blisters (which tend to spray when ruptured), becoming rough and fissured or scaly on old trees. The leaves are flat needle-like, 1.5-3 cm long, dark green above often with a small patch of stomata near the tip, and two white stomatal bands below, and a slightly notched tip. They are arranged spirally on the shoot, but with the leaf bases twisted to appear in two more-or-less horizontal rows. The cones are erect, 4-8 cm long, dark purple, ripening brown and disintegrating to release the winged seeds in September. There are two varieties: - Abies balsamea var. balsamea (Balsam Fir) - bract scales short, not visible on the closed cones. Most of the species' range. - Abies balsamea var. phanerolepis (Bracted Balsam Fir or Canaan Fir) - bract scales longer, visible on the closed cone. The southeast of the species' range, from southernmost Quebec to West Virginia. The name 'Canaan Fir' derives from one of its native localities, the Canaan Valley in West Virginia. Some botanists regard this variety as a natural hybrid between Balsam Fir and Fraser Fir (Abies fraseri), which occurs further south in the Appalachian Mountains. # Ecology On exposed ridges and mountain tops, stands of balsam fir occasionally develop fir waves. Often found in association with black spruce, white spruce, trembling aspen and paper birch. This tree provides food for moose, American red squirrels, crossbills and chickadees, as well as shelter for moose, snowshoe hares, white-tailed deer, ruffed grouse and other small mammals and songbirds. The needles are eaten by some lepidopteran caterpillars, for example the Io moth (Automeris io). # Uses The resin is used to produce Canada balsam, and was traditionally used as a cold remedy. The wood is used for paper manufacture and is also a popular Christmas tree Balsam Fir is the Provincial tree of New Brunswick.	Balsam Fir The Balsam Fir (Abies balsamea) is a North American fir, native to most of eastern and central Canada (Newfoundland west to central Alberta) and the northeastern United States (Minnesota east to Maine, and south in the Appalachian Mountains to West Virginia).[1] It is a small to medium-size evergreen tree typically 14-20 m tall, rarely to 27 m tall, with a narrow conic crown. The bark on young trees is smooth, grey, and with resin blisters (which tend to spray when ruptured), becoming rough and fissured or scaly on old trees. The leaves are flat needle-like, 1.5-3 cm long, dark green above often with a small patch of stomata near the tip, and two white stomatal bands below, and a slightly notched tip. They are arranged spirally on the shoot, but with the leaf bases twisted to appear in two more-or-less horizontal rows. The cones are erect, 4-8 cm long, dark purple, ripening brown and disintegrating to release the winged seeds in September. There are two varieties: - Abies balsamea var. balsamea (Balsam Fir) - bract scales short, not visible on the closed cones. Most of the species' range. - Abies balsamea var. phanerolepis (Bracted Balsam Fir or Canaan Fir) - bract scales longer, visible on the closed cone. The southeast of the species' range, from southernmost Quebec to West Virginia. The name 'Canaan Fir' derives from one of its native localities, the Canaan Valley in West Virginia. Some botanists regard this variety as a natural hybrid between Balsam Fir and Fraser Fir (Abies fraseri), which occurs further south in the Appalachian Mountains. ## Ecology On exposed ridges and mountain tops, stands of balsam fir occasionally develop fir waves. Often found in association with black spruce, white spruce, trembling aspen and paper birch. This tree provides food for moose, American red squirrels, crossbills and chickadees, as well as shelter for moose, snowshoe hares, white-tailed deer, ruffed grouse and other small mammals and songbirds. The needles are eaten by some lepidopteran caterpillars, for example the Io moth (Automeris io). ## Uses The resin is used to produce Canada balsam, and was traditionally used as a cold remedy. The wood is used for paper manufacture and is also a popular Christmas tree Balsam Fir is the Provincial tree of New Brunswick.	https://www.wikidoc.org/index.php/Balsam_Fir
479827368fbf63141adfeb9fe37122b4579fd5ff	wikidoc	Bambuterol	Bambuterol # Overview Bambuterol is a long acting beta-adrenoceptor agonist (LABA) used in the treatment of asthma; it also is a prodrug of terbutaline. Commercially, the AstraZeneca pharmaceutical company produces and markets bambuterol as Bambec and Oxeol (INN). # Indications As other LABAs, bambuterol is used in the long-term management of persistent asthma. It should not be used as a rescue medication for short-term relief of asthma symptoms. ## Contraindications Bambuterol is contraindicated in pregnancy and in people with seriously impaired liver function. It can be used by people with renal impairment, but dose adjustments are necessary. # Adverse effects The adverse effect profile of bambuterol is similar to that of salbutamol, and may include fatigue, nausea, palpitations, headache, dizziness and tremor. # Interactions Concomitant administration of bambuterol with corticosteroids, diuretics, and xanthine derivatives (such as theophylline) increases the risk of hypokalemia (decreased levels of potassium in the blood). Bambuterol acts as a cholinesterase inhibitor, and can prolong the duration of action of suxamethonium (succinylcholine) and other drugs whose breakdown in the body depends on cholinesterase function. Butyrylcholinesterase activity returns to normal approximately two weeks after bambuterol is stopped. It can also enhance the effects of non-depolarizing neuromuscular blockers, such as vecuronium bromide.	Bambuterol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Bambuterol is a long acting beta-adrenoceptor agonist (LABA) used in the treatment of asthma; it also is a prodrug of terbutaline. Commercially, the AstraZeneca pharmaceutical company produces and markets bambuterol as Bambec and Oxeol (INN).[1] # Indications As other LABAs, bambuterol is used in the long-term management of persistent asthma.[1] It should not be used as a rescue medication for short-term relief of asthma symptoms. ## Contraindications Bambuterol is contraindicated in pregnancy and in people with seriously impaired liver function. It can be used by people with renal impairment, but dose adjustments are necessary.[1] # Adverse effects The adverse effect profile of bambuterol is similar to that of salbutamol, and may include fatigue, nausea, palpitations, headache, dizziness and tremor.[1] # Interactions Concomitant administration of bambuterol with corticosteroids, diuretics, and xanthine derivatives (such as theophylline) increases the risk of hypokalemia (decreased levels of potassium in the blood).[2] Bambuterol acts as a cholinesterase inhibitor, and can prolong the duration of action of suxamethonium (succinylcholine) and other drugs whose breakdown in the body depends on cholinesterase function.[1] Butyrylcholinesterase activity returns to normal approximately two weeks after bambuterol is stopped.[3] It can also enhance the effects of non-depolarizing neuromuscular blockers, such as vecuronium bromide.[2]	https://www.wikidoc.org/index.php/Bambuterol
222c2736e8e5361cdd3f724b73979de9bfa8be8c	wikidoc	Bananadine	Bananadine Bananadine is a fictional psychoactive substance which is allegedly extracted from banana peels. A recipe for its extraction from banana peel was originally published as a hoax in the Berkeley Barb in March 1967. It became more widely known when William Powell, believing it to be true, reproduced the method in The Anarchist Cookbook in 1970 under the name "Musa Sapientum Bananadine" (referring to the banana's binomial nomenclature). Researchers at New York University have found that banana peel contains no intoxicating chemicals, and that smoking it produces only a placebo effect. Over the years, bananadine has become a popular urban legend. # Chemicals in Bananas Banana peels, however, do contain the nonpsychoactive neurotransmitters tyramine and dopamine in significant amounts that if ingested are enough to affect people taking MAOIs. These chemicals are present in many foods at higher concentrations, and users of MAOIs are counseled to avoid them. The most characteristic effect of the interaction is a massive increase in blood pressure, leading to a hypertensive crisis, and possibly arrhythmia and death. Bananas contain tryptophan which, when ingested, increases levels of serotonin in the body. This can lead to various mood-altering effects (Leathwood and Pollet, 1982) including a reduction in depression (Sainio et al., 1996). As well, Xiao et al. (1998) found that eating just two bananas a day for three days increased levels of serotonin in the blood by 16%. However, there is no mention in the literature of tryptophan having any hallucinogenic effects; it has, in fact, been used to reduce hallucinations in patients with mental disorders (Sainio et al., 1996). It is also debatable whether smoking tryptophan would be successful as a method of administration. # Bananadine in Popular Culture Donovan's hit single "Mellow Yellow" was released the same month as the Berkeley Barb hoax, and for years it was (wrongly) assumed "Mellow Yellow" was the source for this myth. In an October 2005 interview on the National Public Radio program "Fresh Air", Donovan said that it was actually the folk singer Country Joe McDonald who had started the rumor in San Francisco, one week before the release of Donovan's song. Mr. McDonald has told a similar story, including the side effect of a shortage of bananas in all of Berkeley following the concert that started the rumor, as all available bananas were bought by concert-goers for experimentation (2003, Palms Playhouse, Winters, CA). The myth was brought to attention once more in the late 1980s, when the satiric punk group The Dead Milkmen released a song concerning the effects of smoking banana peels. Even the Food and Drug Administration (FDA) investigated. In the inner sleeve of Experience, the first full length album by British band The Prodigy, Leeroy Thornhill is quoted saying "Respect to everyone I've met, you're welcome round to smoke some Banana skins anytime". The Ray Stevens song "Thirty-Five Year Old Hippie Class Reunion" alludes to this hoax. There is a recurring exchange: "What happened to it?" "We smoked it..." about increasingly improbable things, until at the end of the song the two characters enthusiastically consider smoking the entire contents of a pet store.	Bananadine Bananadine is a fictional psychoactive substance which is allegedly extracted from banana peels. A recipe for its extraction from banana peel was originally published as a hoax in the Berkeley Barb in March 1967.[verification needed] It became more widely known when William Powell, believing it to be true, reproduced the method in The Anarchist Cookbook in 1970 under the name "Musa Sapientum Bananadine" (referring to the banana's binomial nomenclature). Researchers at New York University have found that banana peel contains no intoxicating chemicals, and that smoking it produces only a placebo effect. Over the years, bananadine has become a popular urban legend. # Chemicals in Bananas Banana peels, however, do contain the nonpsychoactive neurotransmitters tyramine and dopamine in significant amounts that if ingested are enough to affect people taking MAOIs. [1] These chemicals are present in many foods at higher concentrations, and users of MAOIs are counseled to avoid them. The most characteristic effect of the interaction is a massive increase in blood pressure, leading to a hypertensive crisis, and possibly arrhythmia and death.[1] Bananas contain tryptophan which, when ingested, increases levels of serotonin in the body. This can lead to various mood-altering effects (Leathwood and Pollet, 1982) including a reduction in depression (Sainio et al., 1996). As well, Xiao et al. (1998) found that eating just two bananas a day for three days increased levels of serotonin in the blood by 16%. However, there is no mention in the literature of tryptophan having any hallucinogenic effects; it has, in fact, been used to reduce hallucinations in patients with mental disorders (Sainio et al., 1996). It is also debatable whether smoking tryptophan would be successful as a method of administration. # Bananadine in Popular Culture Donovan's hit single "Mellow Yellow" was released the same month as the Berkeley Barb hoax, and for years it was (wrongly) assumed "Mellow Yellow" was the source for this myth. In an October 2005 interview on the National Public Radio program "Fresh Air", Donovan said that it was actually the folk singer Country Joe McDonald who had started the rumor in San Francisco, one week before the release of Donovan's song. Mr. McDonald has told a similar story, including the side effect of a shortage of bananas in all of Berkeley following the concert that started the rumor, as all available bananas were bought by concert-goers for experimentation (2003, Palms Playhouse, Winters, CA). The myth was brought to attention once more in the late 1980s, when the satiric punk group The Dead Milkmen released a song concerning the effects of smoking banana peels. Even the Food and Drug Administration (FDA) investigated. In the inner sleeve of Experience, the first full length album by British band The Prodigy, Leeroy Thornhill is quoted saying "Respect to everyone I've met, you're welcome round to smoke some Banana skins anytime". The Ray Stevens song "Thirty-Five Year Old Hippie Class Reunion" alludes to this hoax. There is a recurring exchange: "What happened to it?" "We smoked it..." about increasingly improbable things, until at the end of the song the two characters enthusiastically consider smoking the entire contents of a pet store.	https://www.wikidoc.org/index.php/Bananadine
6490aab3ae2bdcb3b06d40c7ab2146cd75bf7859	wikidoc	Neutrophil	Neutrophil # Overview Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of white blood cells and form an integral part of the immune system. Their name arrives from staining characteristics on hematoxylin and eosin (H&E) histological preparations. Whereas basophilic cellular components stain dark blue and eosinophilic components stain bright red, neutrophilic components stain a neutral pink. These phagocytes are normally found in the blood stream. However, during the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils leave the vasculature and migrate toward the site of inflammation in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowish appearance. Neutrophils react within an hour of tissue injury and are the hallmark of acute inflammation. # Measurement of neutrophils Neutrophil granulocytes have an average volume of 330 femtoliters (fl) and a diameter of 12-15 micrometers (µm) in peripheral blood smears. With the eosinophil and the basophil, they form the class of polymorphonuclear cells (PMNs), named for the nucleus's characteristic multilobulated shape (as compared to lymphocytes and monocytes, the other types of white cells). Neutrophils are the most abundant white blood cells; they account for 70% of all white blood cells (leukocytes). The stated normal range for blood counts varies between laboratories, but a neutrophil count of 2.5-7.5 x 109/L is a standard normal range. People of African and Middle Eastern descent may have lower counts which are still normal. A report may divide neutrophils into segmented neutrophils and bands. # Lifespan The average halflife of a non-activated neutrophil in the circulation is about 4-10 hours. Upon activation, they marginate (position themselves adjacent to the blood vessel endothelium), undergo selectin dependent capture followed by integrin dependent adhesion after which they migrate into tissues, where they survive for 1-2 days. Neutrophils are much more numerous than the longer-lived monocyte/macrophages. The first phagocyte a pathogen (disease-causing microorganism) is likely to encounter is a neutrophil. Some experts feel that the short lifetime of neutrophils is an evolutionary adaptation to minimize propagation of those pathogens that parasitize phagocytes. The more time such parasites spend outside a host cell, the more likely they will be destroyed by some component of the body's defenses. However, because neutrophil antimicrobial products can also damage host tissues, other authorities feel that their short life is an adaptation to limit damage to the host during inflammation. # Chemotaxis Neutrophils undergo a process called chemotaxis that allows them to migrate toward sites of infection or inflammation. Cell surface receptors are able to detect chemical gradients of molecules such as interleukin-8 (IL-8), interferon gamma (IFN-gamma), and C5a which these cells use to direct the path of their migration. # Function Being highly motile, neutrophils quickly congregate at a focus of infection, attracted by cytokines expressed by activated endothelium, mast cells and macrophages. ## Phagocytosis Neutrophils are phagocytes, capable of ingesting microorganisms or particles. They can internalise and kill many microbes, each phagocytic event resulting in the formation of a phagosome into which reactive oxygen species and hydrolytic enzymes are secreted. The consumption of oxygen during the generation of reactive oxygen species has been termed the "respiratory burst," although it actually has nothing to do with respiration or energy production. The respiratory burst involves the activation of the enzyme NADPH oxidase, which produces large quantities of superoxide, a reactive oxygen species. Superoxide dismutates, spontaneously or through catalysis via the enzyme catalase, to hydrogen peroxide, which is then converted to hypochlorous acid (HOCl, also known as chlorine bleach) by the green heme enzyme myeloperoxidase. It is thought that the bactericidal properties of HOCl are enough to kill bacteria phagocytosed by the neutrophil, but this has not been proven conclusively. ## Degranulation Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation: ## NETs There is controversy about whether neutrophils can also extrude neutrophil extracellular traps (NETs), a web of fibers composed of chromatin and serine proteases that trap and kill microbes extracellularly. It is suggested that NETs provide a high local concentration of antimicrobial components and bind, disarm, and kill microbes independent of phagocytic uptake. In addition to their possible antimicrobial properties, NETs may serve as a physical barrier that prevents further spread of pathogens. Recently, NETs have been shown to play a role in inflammatory diseases, as NETs could be detected in preeclampsia, a pregnancy related inflammatory disorder in which neutrophils are known to be activated. # Role in disease Low neutrophil counts are termed "neutropenia". This can be congenital (genetic disorder) or it can develop later, as in the case of aplastic anemia or some kinds of leukemia. It can also be a side-effect of medication, most prominently chemotherapy. Neutropenia predisposes heavily for infection. Finally, neutropenia can be the result of colonization by intracellular neutrophilic parasites. Functional disorders of neutrophils are often hereditary. They are disorders of phagocytosis or deficiencies in the respiratory burst (as in chronic granulomatous disease, a rare immune deficiency, and myeloperoxidase deficiency). In alpha 1-antitrypsin deficiency, the important neutrophil enzyme elastase is not adequately inhibited by alpha 1-antitrypsin, leading to excessive tissue damage in the presence of inflammation - most prominently pulmonary emphysema. In Familial Mediterranean fever (FMF), a mutation in the pyrin (or marenostrin) gene, which is expressed mainly in neutrophil granulocytes, leads to a constitutionally active acute phase response and causes attacks of fever, arthralgia, peritonitis and - eventually - amyloidosis.	Neutrophil Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of white blood cells and form an integral part of the immune system. Their name arrives from staining characteristics on hematoxylin and eosin (H&E) histological preparations. Whereas basophilic cellular components stain dark blue and eosinophilic components stain bright red, neutrophilic components stain a neutral pink. These phagocytes are normally found in the blood stream. However, during the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils leave the vasculature and migrate toward the site of inflammation in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowish appearance. Neutrophils react within an hour of tissue injury and are the hallmark of acute inflammation.[1] # Measurement of neutrophils Neutrophil granulocytes have an average volume of 330 femtoliters (fl) and a diameter of 12-15 micrometers (µm) in peripheral blood smears. With the eosinophil and the basophil, they form the class of polymorphonuclear cells (PMNs), named for the nucleus's characteristic multilobulated shape (as compared to lymphocytes and monocytes, the other types of white cells). Neutrophils are the most abundant white blood cells; they account for 70% of all white blood cells (leukocytes). The stated normal range for blood counts varies between laboratories, but a neutrophil count of 2.5-7.5 x 109/L is a standard normal range. People of African and Middle Eastern descent may have lower counts which are still normal. A report may divide neutrophils into segmented neutrophils and bands. # Lifespan The average halflife of a non-activated neutrophil in the circulation is about 4-10 hours. Upon activation, they marginate (position themselves adjacent to the blood vessel endothelium), undergo selectin dependent capture followed by integrin dependent adhesion after which they migrate into tissues, where they survive for 1-2 days. Neutrophils are much more numerous than the longer-lived monocyte/macrophages. The first phagocyte a pathogen (disease-causing microorganism) is likely to encounter is a neutrophil. Some experts feel that the short lifetime of neutrophils is an evolutionary adaptation to minimize propagation of those pathogens that parasitize phagocytes. The more time such parasites spend outside a host cell, the more likely they will be destroyed by some component of the body's defenses. However, because neutrophil antimicrobial products can also damage host tissues, other authorities feel that their short life is an adaptation to limit damage to the host during inflammation. # Chemotaxis Neutrophils undergo a process called chemotaxis that allows them to migrate toward sites of infection or inflammation. Cell surface receptors are able to detect chemical gradients of molecules such as interleukin-8 (IL-8), interferon gamma (IFN-gamma), and C5a which these cells use to direct the path of their migration. # Function Being highly motile, neutrophils quickly congregate at a focus of infection, attracted by cytokines expressed by activated endothelium, mast cells and macrophages. ## Phagocytosis Neutrophils are phagocytes, capable of ingesting microorganisms or particles. They can internalise and kill many microbes, each phagocytic event resulting in the formation of a phagosome into which reactive oxygen species and hydrolytic enzymes are secreted. The consumption of oxygen during the generation of reactive oxygen species has been termed the "respiratory burst," although it actually has nothing to do with respiration or energy production. The respiratory burst involves the activation of the enzyme NADPH oxidase, which produces large quantities of superoxide, a reactive oxygen species. Superoxide dismutates, spontaneously or through catalysis via the enzyme catalase, to hydrogen peroxide, which is then converted to hypochlorous acid (HOCl, also known as chlorine bleach) by the green heme enzyme myeloperoxidase. It is thought that the bactericidal properties of HOCl are enough to kill bacteria phagocytosed by the neutrophil, but this has not been proven conclusively. ## Degranulation Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation: ## NETs There is controversy about whether neutrophils can also extrude neutrophil extracellular traps (NETs), a web of fibers composed of chromatin and serine proteases that trap and kill microbes extracellularly. It is suggested that NETs provide a high local concentration of antimicrobial components and bind, disarm, and kill microbes independent of phagocytic uptake. In addition to their possible antimicrobial properties, NETs may serve as a physical barrier that prevents further spread of pathogens. Recently, NETs have been shown to play a role in inflammatory diseases, as NETs could be detected in preeclampsia, a pregnancy related inflammatory disorder in which neutrophils are known to be activated. # Role in disease Low neutrophil counts are termed "neutropenia". This can be congenital (genetic disorder) or it can develop later, as in the case of aplastic anemia or some kinds of leukemia. It can also be a side-effect of medication, most prominently chemotherapy. Neutropenia predisposes heavily for infection. Finally, neutropenia can be the result of colonization by intracellular neutrophilic parasites. Functional disorders of neutrophils are often hereditary. They are disorders of phagocytosis or deficiencies in the respiratory burst (as in chronic granulomatous disease, a rare immune deficiency, and myeloperoxidase deficiency). In alpha 1-antitrypsin deficiency, the important neutrophil enzyme elastase is not adequately inhibited by alpha 1-antitrypsin, leading to excessive tissue damage in the presence of inflammation - most prominently pulmonary emphysema. In Familial Mediterranean fever (FMF), a mutation in the pyrin (or marenostrin) gene, which is expressed mainly in neutrophil granulocytes, leads to a constitutionally active acute phase response and causes attacks of fever, arthralgia, peritonitis and - eventually - amyloidosis.	https://www.wikidoc.org/index.php/Bands
ba7e11bff027448a5c81be2e24b1f39ccb80b863	wikidoc	Bar (unit)	Bar (unit) The bar (symbol bar), decibar (symbol dbar) and the millibar (symbol mbar, also mb) are units of pressure. They are not SI units, nor are they cgs units, but they are accepted for use with the SI. The bar is still widely used in descriptions of pressure because it is about the same as atmospheric pressure. # Definition The bar, decibar and millibar are defined as: - 1 bar = 100 kPa (kilopascals) = 1,000,000 dynes per square centimeter (baryes) - 1 dbar = 0.1 bar = 10 kPa = 100,000 dyn/cm² - 1 mbar = 0.001 bar = 0.1 kPa = 1 hPa = 1,000 dyn/cm² (A pascal is one newton per square meter.) # Origin The word bar has its origin in the Greek word βάρος (baros), meaning weight. Its official symbol is "bar"; the earlier "b" is now deprecated, but still often seen especially in "mb" rather than the proper "mbar" for millibars. The bar and millibar were introduced by Sir Napier Shaw in 1909 and internationally adopted in 1929. # Discussion Atmospheric air pressure is often given in millibars where "standard" sea level pressure is defined as 1013.25 mbar (hPa), equal to 1.01325 bar. Despite millibars not being an SI unit, they are still used locally in meteorology in some countries to describe atmospheric pressure. The SI unit is the pascal (Pa), with 1 mbar = 100 Pa = 1 hPa = 0.1 kPa. Meteorologists worldwide have long measured air pressure in millibars. After the introduction of SI units, others use hectopascals (which are equivalent to millibars) so they could stick to the same numeric scale. Similar pressures are given in kilopascals in practically all other fields, where the hecto prefix is hardly ever used. In particular, Canadian weather reports use kilopascals (which could also be called centibars). Americans are familiar with the millibar in US reports of hurricanes and other cyclonic storms, where lower central pressure generally means higher winds and a stronger storm. In some countries, pressure is measured with reference to atmospheric pressure. This is gauge pressure and denoted by barg, often written with no spaces, spoken "bar gauge", and sometimes using symbols such as 'bar(g)'. For example, if someone says that their car tyres are pressurised to 2.3 bar they actually mean bar gauge: the pressure in the tyre is really 3.3 bar, but only 2.3 bar above atmospheric, which is the scale a tyre gauge would read. When absolute pressure is desired, it is sometimes denoted 'bara' or 'bar(a)' for "bar absolute". The alteration of units of measure for this purpose is now deprecated, with qualification of the physical property being preferred, e.g., "The gauge pressure is 2.3 bar; the absolute pressure is 3.3 bar". In water, there is an approximate numerical correspondence between the change in pressure in decibars and the change in depth from the sea surface in meters. Specifically, an increase of 1 decibar occurs for every 1.019716 m increase in depth close to the surface. As a result, decibars are commonly used in oceanography. Unicode has a character for "mb": (Template:Unicode), but exists only for compatibility with legacy Asian encodings. There is also a character "bar": Template:Unicode.	Bar (unit) The bar (symbol bar), decibar (symbol dbar) and the millibar (symbol mbar, also mb) are units of pressure. They are not SI units, nor are they cgs units, but they are accepted for use with the SI. The bar is still widely used in descriptions of pressure because it is about the same as atmospheric pressure. # Definition The bar, decibar and millibar are defined as: - 1 bar = 100 kPa (kilopascals) = 1,000,000 dynes per square centimeter (baryes) - 1 dbar = 0.1 bar = 10 kPa = 100,000 dyn/cm² - 1 mbar = 0.001 bar = 0.1 kPa = 1 hPa = 1,000 dyn/cm² (A pascal is one newton per square meter.) # Origin The word bar has its origin in the Greek word βάρος (baros), meaning weight. Its official symbol is "bar"; the earlier "b" is now deprecated, but still often seen especially in "mb" rather than the proper "mbar" for millibars. The bar and millibar were introduced by Sir Napier Shaw in 1909 and internationally adopted in 1929. # Discussion Atmospheric air pressure is often given in millibars where "standard" sea level pressure is defined as 1013.25 mbar (hPa), equal to 1.01325 bar. Despite millibars not being an SI unit, they are still used locally in meteorology in some countries to describe atmospheric pressure. The SI unit is the pascal (Pa), with 1 mbar = 100 Pa = 1 hPa = 0.1 kPa. Meteorologists worldwide have long measured air pressure in millibars. After the introduction of SI units, others use hectopascals (which are equivalent to millibars) so they could stick to the same numeric scale. Similar pressures are given in kilopascals in practically all other fields, where the hecto prefix is hardly ever used. In particular, Canadian weather reports use kilopascals (which could also be called centibars). Americans are familiar with the millibar in US reports of hurricanes and other cyclonic storms, where lower central pressure generally means higher winds and a stronger storm. In some countries, pressure is measured with reference to atmospheric pressure. This is gauge pressure and denoted by barg, often written with no spaces, spoken "bar gauge", and sometimes using symbols such as 'bar(g)'. For example, if someone says that their car tyres are pressurised to 2.3 bar they actually mean bar gauge: the pressure in the tyre is really 3.3 bar, but only 2.3 bar above atmospheric, which is the scale a tyre gauge would read. When absolute pressure is desired, it is sometimes denoted 'bara' or 'bar(a)' for "bar absolute". The alteration of units of measure for this purpose is now deprecated, with qualification of the physical property being preferred, e.g., "The gauge pressure is 2.3 bar; the absolute pressure is 3.3 bar". In water, there is an approximate numerical correspondence between the change in pressure in decibars and the change in depth from the sea surface in meters. Specifically, an increase of 1 decibar occurs for every 1.019716 m increase in depth close to the surface. As a result, decibars are commonly used in oceanography. Unicode has a character for "mb": (Template:Unicode), but exists only for compatibility with legacy Asian encodings. There is also a character "bar": Template:Unicode. Template:Pressure Units # External links - Official SI website: Table 8. Non-SI units accepted for use with the SI - Conversion factors from bar to various pressure units	https://www.wikidoc.org/index.php/Bar_(unit)
4cb1f8b91b2fbf8f8d1241746807fe546ffd8b51	wikidoc	Bariatrics	Bariatrics Bariatrics is the branch of medicine that deals with the causes, prevention, and treatment of obesity. The term bariatrics was created around 1965, from the Greek root baro ("weight," as in barometer) and suffix -iatrics ("a branch of medicine," as in pediatrics). Besides the pharmacotherapy of obesity, it is concerned with obesity surgery. Overweight and obesity are rising medical problems of pandemic proportions. There are many detrimental health effects of obesity: heart disease, diabetes, many types of cancer, asthma, obstructive sleep apnea, chronic musculoskeletal problems, etc. There is also a clear effect of obesity on mortality, though this is not so clear for those who are overweight. # Diagnosis Although not a Direct measure of body fat, the Body Mass Index is widely adopted and promoted as a marker for excess body weight. However, it is not flawless: a very muscular person may be assessed as obese, and an elderly person with low body weight but high body fat (this can happen due to low muscle mass and bone density) may be assessed as healthy. Other markers for the evaluation of obesity include waist circumference (associated with central obesity), and a patient's risk factors for diseases and conditions associated with obesity. Besides these indirect methods, body fat can also be measured directly. # General aspects of treatment Although diet, exercise, behavior therapy and anti-obesity drugs are first-line treatment, medical therapy for severe obesity has limited short-term success and almost nonexistent long-term success. Therefore, obesity surgery (or bariatric surgery) has been a popular treatment in the war against obesity. Weight loss surgery generally results in greater weight loss than conventional treatment, and leads to improvements in quality of life and obesity related diseases such as hypertension and diabetes. # Healthy lifestyle Healthy lifestyle changes such as dieting and improvements in health behavior can be fostered by methods of patient engagement. # Anti-obesity drugs If diet and exercise are ineffective alone, anti-obesity drugs are a choice for some patients. Prescription weight loss drugs are recommended only for short-term use, and thus are of limited usefulness for extremely obese patients, who may need to reduce weight over months or years. # Bariatric surgery Before someone can become eligible for bariatric surgery, certain criteria must be met. The basic criteria are an understanding of the operation and the lifestyle changes the patient will need to make, and either: - a body mass index (BMI) of 40 or more, which is about 45 kg (100 pounds) overweight for men and 35 kg (80 pounds) for women; or - a BMI between 35 and 39.9 and a serious obesity-related health problem such as type 2 diabetes, heart disease, or severe sleep apnea (when breathing stops for short periods during sleep) Past studies found that 10 percent to 20 percent of bariatric surgery patients had complications while they were in the hospital. In 2006, federal researchers found that 39.6 percent of patients had complications within 180 days of surgery. The most common complications are - a composite of gastrointestinal symptoms including vomiting, diarrhea, dysphagia, and reflux (20%) - anastomotic leaking (at the surgical connections between the stomach and the intestine) (12%) - abdominal hernia (7%) - and "infections" (6%). About 7% of patients were readmitted to the hospital within 6 months to treat complications specific to the bariatric procedure. There were 212 in-hospital deaths out of an estimated 104,702 adults who underwent obesity surgery in 2003, or a rate of 0.2 per cent. The prevalence of extreme obesity (body mass index > or = 40 kg/m²) in the United States in 2003-2004 was 2.8% in men and 6.9% in women. This suggests millions of people are in the weight range for potential therapy with bariatric surgery. Laparoscopic surgery has become an important addition to this field of surgery, and demand soars, amidst scientific and ethical questions. The number of Americans having weight-loss surgery more than quadrupled between 1998 and 2002—from 13,386 to 71,733—according to a study by the Agency for Healthcare Research and Quality. ## Surgical procedures There are a number of surgical options available to treat obesity, each with their advantages and pitfalls. In general, weight reduction can be accomplished, but one must consider operative risk (including mortality) and side effects. Usually, these procedures can be carried out safely. Procedures can be grouped in three main categories: - predominantly malabsorptive procedures: although also reducing stomach size, these operations are based mainly on malabsorption. Biliopancreatic Diversion (Scopinaro procedure - rare) Jejuno-ileal bypass (no longer performed) - Biliopancreatic Diversion (Scopinaro procedure - rare) - Jejuno-ileal bypass (no longer performed) - predominantly restrictive procedures: this kind of surgery primarily reduces stomach size Vertical Banded Gastroplasty (Mason procedure, stomach stapling) Adjustable gastric band (or "Lap Band") Sleeve gastrectomy - Vertical Banded Gastroplasty (Mason procedure, stomach stapling) - Adjustable gastric band (or "Lap Band") - Sleeve gastrectomy - Mixed procedures: applying both techniques simultaneously gastric bypass surgery, like Roux-en-Y gastric bypass Sleeve gastrectomy with Duodenal Switch Implantable Gastric Stimulation - gastric bypass surgery, like Roux-en-Y gastric bypass - Sleeve gastrectomy with Duodenal Switch - Implantable Gastric Stimulation # Footnotes - ↑ The American Heritage Dictionary of the English Language, 4th edition, Houghton (2000): "Bariatrics" Retrived 14 Feb. 2006 - ↑ Dictionary.com, based on Random House Unabridged Dictionary, Random House (2006): Retrieved 15 Apr. 2006 - ↑ Reynolds K, He J. Epidemiology of the metabolic syndrome.Am J Med Sci 2005;330:273-9. PMID 16355011 - ↑ Hedley AA, Ogden CL, Johnson CL, et al. 2004. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA ; 291: 2847–50. PMID 15199035 - ↑ WHO factsheet on obesity - ↑ Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess deaths associated with underweight, overweight, and obesity. JAMA 2005; 293: 1861-7. - ↑ Obesity: preventing and managing the global epidemic. Geneva, World Health Organization (WHO Technical Report Series, No. 894). - ↑ Jump up to: 8.0 8.1 Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report. NIH Publication NO. 98-4083, september 1998. NATIONAL INSTITUTES OF HEALTH National Heart, Lung, and Blood Institute in cooperation with The National Institute of Diabetes and Digestive and Kidney Diseases. - ↑ Jump up to: 9.0 9.1 Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference Statement. Am J Clin Nutr 1992;55(S2):615S-619S. PMID 1733140 - ↑ Colquitt J, Clegg A, Sidhu M, Royle P. Surgery for morbid obesity. Cochrane Database Syst Rev 2003; 2: CD003641. PMID 12804481 - ↑ Gastrointestinal surgery for severe obesity. U.S. Department of Health and Human Services, National Institutes of Health. NIH Publication No. 04-4006, December 2004. Agency for Healthcare Research and Quality: Obesity Surgery Complication Rates Higher Over Time. Press Release, July 24, 2006. Retrieved July 24, 2006 - ↑ Encinosa WE, Bernard DM, Chen CC, Steiner CA (2006). "Healthcare utilization and outcomes after bariatric surgery" (Abstract). Medical Care. 44(8): 706–12. Retrieved 2006-08-08.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 2006; 295:1549-55. PMID 16595758 - ↑ Mitka M. Surgery for obesity: demand soars amid scientific, ethical questions. JAMA 2003; 289: 1761-2. - ↑ Agency for Healthcare Research and Quality: AHRQ Study Finds Weight-loss Surgeries Quadrupled in Five Years. Press Release, July 12, 2005 Retrieved July 24, 2006 - ↑ Nguyen NT et al. Result of a national audit of bariatric surgery performed at academic centers: a 2004 University HealthSystem Consortium Benchmarking Project. Arch Surg 2006; 141: 445-9. PMID 16702515 - ↑ Abell TL, Minocha A. Gastrointestinal complications of bariatric surgery: diagnosis and therapy. Am J Med Sci 2006;331: 214-8.	Bariatrics Template:Globalize/USA Bariatrics is the branch of medicine that deals with the causes, prevention, and treatment of obesity.[1] The term bariatrics was created around 1965,[2] from the Greek root baro ("weight," as in barometer) and suffix -iatrics ("a branch of medicine," as in pediatrics). Besides the pharmacotherapy of obesity, it is concerned with obesity surgery. Overweight and obesity are rising medical problems of pandemic proportions.[3][4] There are many detrimental health effects of obesity:[5] heart disease, diabetes, many types of cancer, asthma, obstructive sleep apnea, chronic musculoskeletal problems, etc. There is also a clear effect of obesity on mortality, though this is not so clear for those who are overweight.[6] # Diagnosis Although not a Direct measure of body fat, the Body Mass Index is widely adopted and promoted as a marker for excess body weight.[7] However, it is not flawless: a very muscular person may be assessed as obese, and an elderly person with low body weight but high body fat (this can happen due to low muscle mass and bone density) may be assessed as healthy. Other markers for the evaluation of obesity include waist circumference (associated with central obesity), and a patient's risk factors for diseases and conditions associated with obesity.[8] Besides these indirect methods, body fat can also be measured directly. # General aspects of treatment Although diet, exercise, behavior therapy and anti-obesity drugs are first-line treatment,[8] medical therapy for severe obesity has limited short-term success and almost nonexistent long-term success.[9] Therefore, obesity surgery (or bariatric surgery) has been a popular treatment in the war against obesity. Weight loss surgery generally results in greater weight loss than conventional treatment, and leads to improvements in quality of life and obesity related diseases such as hypertension and diabetes.[10] # Healthy lifestyle Healthy lifestyle changes such as dieting and improvements in health behavior can be fostered by methods of patient engagement. # Anti-obesity drugs If diet and exercise are ineffective alone, anti-obesity drugs are a choice for some patients. Prescription weight loss drugs are recommended only for short-term use, and thus are of limited usefulness for extremely obese patients, who may need to reduce weight over months or years. # Bariatric surgery Before someone can become eligible for bariatric surgery, certain criteria must be met.[9] The basic criteria are an understanding of the operation and the lifestyle changes the patient will need to make, and either:[11] - a body mass index (BMI) of 40 or more, which is about 45 kg (100 pounds) overweight for men and 35 kg (80 pounds) for women; or - a BMI between 35 and 39.9 and a serious obesity-related health problem such as type 2 diabetes, heart disease, or severe sleep apnea (when breathing stops for short periods during sleep) Past studies found that 10 percent to 20 percent of bariatric surgery patients had complications while they were in the hospital. In 2006, federal researchers found that 39.6 percent of patients had complications within 180 days of surgery. The most common complications are - a composite of gastrointestinal symptoms including vomiting, diarrhea, dysphagia, and reflux (20%) - anastomotic leaking (at the surgical connections between the stomach and the intestine) (12%) - abdominal hernia (7%) - and "infections" (6%). About 7% of patients were readmitted to the hospital within 6 months to treat complications specific to the bariatric procedure. There were 212 in-hospital deaths out of an estimated 104,702 adults who underwent obesity surgery in 2003, or a rate of 0.2 per cent.[12][13] The prevalence of extreme obesity (body mass index > or = 40 kg/m²) in the United States in 2003-2004 was 2.8% in men and 6.9% in women.[14] This suggests millions of people are in the weight range for potential therapy with bariatric surgery. Laparoscopic surgery has become an important addition to this field of surgery, and demand soars, amidst scientific and ethical questions.[15] The number of Americans having weight-loss surgery more than quadrupled between 1998 and 2002—from 13,386 to 71,733—according to a study by the Agency for Healthcare Research and Quality.[16] ## Surgical procedures There are a number of surgical options available to treat obesity, each with their advantages and pitfalls. In general, weight reduction can be accomplished, but one must consider operative risk (including mortality) and side effects. Usually, these procedures can be carried out safely.[17] Procedures can be grouped in three main categories:[18] - predominantly malabsorptive procedures: although also reducing stomach size, these operations are based mainly on malabsorption. Biliopancreatic Diversion (Scopinaro procedure - rare) Jejuno-ileal bypass (no longer performed) - Biliopancreatic Diversion (Scopinaro procedure - rare) - Jejuno-ileal bypass (no longer performed) - predominantly restrictive procedures: this kind of surgery primarily reduces stomach size Vertical Banded Gastroplasty (Mason procedure, stomach stapling) Adjustable gastric band (or "Lap Band") Sleeve gastrectomy - Vertical Banded Gastroplasty (Mason procedure, stomach stapling) - Adjustable gastric band (or "Lap Band") - Sleeve gastrectomy - Mixed procedures: applying both techniques simultaneously gastric bypass surgery, like Roux-en-Y gastric bypass Sleeve gastrectomy with Duodenal Switch Implantable Gastric Stimulation - gastric bypass surgery, like Roux-en-Y gastric bypass - Sleeve gastrectomy with Duodenal Switch - Implantable Gastric Stimulation # Footnotes - ↑ The American Heritage Dictionary of the English Language, 4th edition, Houghton (2000): "Bariatrics" Retrived 14 Feb. 2006 - ↑ Dictionary.com, based on Random House Unabridged Dictionary, Random House (2006): [1] Retrieved 15 Apr. 2006 - ↑ Reynolds K, He J. Epidemiology of the metabolic syndrome.Am J Med Sci 2005;330:273-9. PMID 16355011 - ↑ Hedley AA, Ogden CL, Johnson CL, et al. 2004. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA ; 291: 2847–50. PMID 15199035 - ↑ WHO factsheet on obesity - ↑ Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess deaths associated with underweight, overweight, and obesity. JAMA 2005; 293: 1861-7. - ↑ Obesity: preventing and managing the global epidemic. Geneva, World Health Organization (WHO Technical Report Series, No. 894). - ↑ Jump up to: 8.0 8.1 Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report. NIH Publication NO. 98-4083, september 1998. NATIONAL INSTITUTES OF HEALTH National Heart, Lung, and Blood Institute in cooperation with The National Institute of Diabetes and Digestive and Kidney Diseases. - ↑ Jump up to: 9.0 9.1 Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference Statement. Am J Clin Nutr 1992;55(S2):615S-619S. PMID 1733140 - ↑ Colquitt J, Clegg A, Sidhu M, Royle P. Surgery for morbid obesity. Cochrane Database Syst Rev 2003; 2: CD003641. PMID 12804481 - ↑ Gastrointestinal surgery for severe obesity. U.S. Department of Health and Human Services, National Institutes of Health. NIH Publication No. 04-4006, December 2004. - ↑ Agency for Healthcare Research and Quality: Obesity Surgery Complication Rates Higher Over Time. Press Release, July 24, 2006. Retrieved July 24, 2006 - ↑ Encinosa WE, Bernard DM, Chen CC, Steiner CA (2006). "Healthcare utilization and outcomes after bariatric surgery" (Abstract). Medical Care. 44(8): 706–12. Retrieved 2006-08-08.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 2006; 295:1549-55. PMID 16595758 - ↑ Mitka M. Surgery for obesity: demand soars amid scientific, ethical questions. JAMA 2003; 289: 1761-2. - ↑ Agency for Healthcare Research and Quality: AHRQ Study Finds Weight-loss Surgeries Quadrupled in Five Years. Press Release, July 12, 2005 Retrieved July 24, 2006 - ↑ Nguyen NT et al. Result of a national audit of bariatric surgery performed at academic centers: a 2004 University HealthSystem Consortium Benchmarking Project. Arch Surg 2006; 141: 445-9. PMID 16702515 - ↑ Abell TL, Minocha A. Gastrointestinal complications of bariatric surgery: diagnosis and therapy. Am J Med Sci 2006;331: 214-8. # External links - MedLinePlus Portal on Weight Loss Surgery - American Society for Bariatric Surgery - American Society for Bariatric Physicians de:Adipositaschirurgie he:ניתוח בריאטרי Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Bariatric
a63ff3953d48cc9e2258ff71322edaeb6396f055	wikidoc	Bark scale	Bark scale The Bark scale is a psychoacoustical scale proposed by Eberhard Zwicker in 1961. It is named after Heinrich Barkhausen who proposed the first subjective measurements of loudness. The scale ranges from 1 to 24 and corresponds to the first 24 critical bands of hearing. The subsequent band edges are (in Hz) 20, 100, 200, 300, 400, 510, 630, 770, 920, 1080, 1270, 1480, 1720, 2000, 2320, 2700, 3150, 3700, 4400, 5300, 6400, 7700, 9500, 12000, 15500. It is related to, but somewhat less popular than the mel scale. To convert a frequency f (Hz) into Bark use: \mathrm{Bark} = 13 \arctan(0.00076f) + 3.5 \arctan((f/7500)^2) \, -r (traunmuller 1990) \mathrm{Critical band rate (bark)} = - 0.53 \, if result < 2 add 0.15(2-result) if result > 20.1 add 0.22(result-20.1) \mathrm{Critical bandwidth (Hz)} = 52548 / (z^2 - 52.56 z + 690.39) \, with z in bark.	Bark scale The Bark scale is a psychoacoustical scale proposed by Eberhard Zwicker in 1961. It is named after Heinrich Barkhausen who proposed the first subjective measurements of loudness[1]. The scale ranges from 1 to 24 and corresponds to the first 24 critical bands of hearing. The subsequent band edges are (in Hz) 20, 100, 200, 300, 400, 510, 630, 770, 920, 1080, 1270, 1480, 1720, 2000, 2320, 2700, 3150, 3700, 4400, 5300, 6400, 7700, 9500, 12000, 15500. It is related to, but somewhat less popular than the mel scale. To convert a frequency f (Hz) into Bark use: \mathrm{Bark} = 13 \arctan(0.00076f) + 3.5 \arctan((f/7500)^2) \, </math> or (traunmuller 1990) \mathrm{Critical band rate (bark)} = [(26.81 f) / (1960 + f )] - 0.53 \, </math> if result < 2 add 0.15(2-result) if result > 20.1 add 0.22(result-20.1) \mathrm{Critical bandwidth (Hz)} = 52548 / (z^2 - 52.56 z + 690.39) \, </math> with z in bark.	https://www.wikidoc.org/index.php/Bark_scale
b84a7fc662ea48066dbc7b18b2fdd27c6e6ecabd	wikidoc	Baroreflex	Baroreflex # Overview In cardiovascular physiology, the baroreflex or baroreceptor reflex is one of the body's homeostatic mechanisms for maintaining blood pressure. It provides a negative feedback loop in which an elevated blood pressure reflexively causes blood pressure to decrease; similarly, decreased blood pressure depresses the baroreflex, causing blood pressure to rise. The system relies on specialized neurons (baroreceptors) in the aortic arch, carotid sinuses, and elsewhere to monitor changes in blood pressure and relay them to the brainstem. Subsequent changes in blood pressure are mediated by the autonomic nervous system. # Anatomy of the reflex Baroreceptors include those in the auricles of the heart and vena cavae, but the most sensitive baroreceptors are in the carotid sinuses and aortic arch. The carotid sinus baroreceptors are innervated by the glossopharyngeal nerve (CN IX); the aortic arch baroreceptors are innervated by the vagus nerve (CN X). Baroreceptor activity travels along these nerves, which contact the nucleus of the solitary tract (NTS) in the brainstem. The NTS sends excitatory fibers (glutamatergic) to the caudal ventrolateral medulla (CVLM), thus activating the CVLM. The activated CVLM then sends inhibitory fibers (GABAergic) to the rostral ventrolateral medulla (RVLM), thus inhibiting the RVLM. The RVLM is the primary regulator of sympathetic nervous system, sending excitatory fibers (catecholaminergic) to the sympathetic preganglionic neurons in the spinal cord. Hence, when the baroreceptors are activated (by an increased blood pressure), the NTS activates the CVLM, which in turn inhibits the RVLM, thus inhibiting the sympathetic branch of the autonomic nervous system leading to a decrease in blood pressure. Likewise, low blood pressure causes an increase in sympathetic tone via "disinhibition" (less inhibition, hence activation) of the RVLM. The NTS also sends excitatory fibers to the Nucleus ambiguus (vagal nuclei) that regulate the parasympathetic nervous system, aiding in the decrease in sympathetic activity during conditions of elevated blood pressure. # Baroreceptor activation The baroreceptors are stretch-sensitive mechanoreceptors. When blood pressure rises, the carotid and aortic sinuses are distended, resulting in stretch and therefore activation of the baroreceptors. Active baroreceptors fire action potentials ("spikes") more frequently than inactive baroreceptors. The greater the stretch, the more rapidly baroreceptors fire action potentials. These action potentials are relayed to the nucleus of the tractus solitarius (NTS), which uses frequency as a measure of blood pressure. As discussed previously, increased activation of the NTS inhibits the vasomotor center and stimulates the vagal nuclei. The end result of baroreceptor activation is inhibition of the sympathetic nervous system and activation of the parasympathetic nervous system. The sympathetic and parasympathetic branches of the autonomic nervous system have opposing effects on blood pressure. Sympathetic activation leads to an elevation of total peripheral resistance and cardiac output via increased contractility of the heart, heart rate, and arterial vasoconstriction, which tends to increase blood pressure. Conversely, parasympathetic activation leads to a decreased cardiac output via decrease in contractility and heart rate, resulting in a tendency to decrease blood pressure. By coupling sympathetic inhibition and parasympathetic activation, the baroreflex maximizes blood pressure reduction. Sympathetic inhibition leads to a drop in peripheral resistance, while parasympathetic activation leads to a depressed heart rate and contractility. The combined effects will dramatically decrease blood pressure. Similarly, sympathetic activation with parasympathetic inhibition allows the baroreflex to elevate blood pressure. CVRx, Inc., a private company located in Minneapolis, Minnesota, has developed an implantable device to treat patients with high blood pressure that cannot be controlled with medications (resistant hypertension) by electrically activating the baroreceptors. This investigational device is called the Rheos Baroreflex Hypertension Therapy System. It is currently under evaluation in an FDA-regulated, phase III clinical trial. # Set point and tonic activation Baroreceptors are active above the baroreceptor set point at mean arterial pressures (MAP) above approximately 70 mm Hg. When MAP falls below the set point, baroreceptors are almost silent. The baroreceptor set point is not fixed; its value may change with changes in blood pressure. For example, in hypertension, the set point will increase; on the other hand, hypotension will result in a depression of the baroreceptor set point. At a MAP below approximately 50 mm Hg, baroreceptors are completely silent. # Effect on heart rate variability The baroreflex may be responsible for a part of the low-frequency component of heart rate variability, the so called Mayer waves, at 0.1 Hz .	Baroreflex Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In cardiovascular physiology, the baroreflex or baroreceptor reflex is one of the body's homeostatic mechanisms for maintaining blood pressure. It provides a negative feedback loop in which an elevated blood pressure reflexively causes blood pressure to decrease; similarly, decreased blood pressure depresses the baroreflex, causing blood pressure to rise. The system relies on specialized neurons (baroreceptors) in the aortic arch, carotid sinuses, and elsewhere to monitor changes in blood pressure and relay them to the brainstem. Subsequent changes in blood pressure are mediated by the autonomic nervous system. # Anatomy of the reflex Baroreceptors include those in the auricles of the heart and vena cavae, but the most sensitive baroreceptors are in the carotid sinuses and aortic arch. The carotid sinus baroreceptors are innervated by the glossopharyngeal nerve (CN IX); the aortic arch baroreceptors are innervated by the vagus nerve (CN X). Baroreceptor activity travels along these nerves, which contact the nucleus of the solitary tract (NTS) in the brainstem. The NTS sends excitatory fibers (glutamatergic) to the caudal ventrolateral medulla (CVLM), thus activating the CVLM. The activated CVLM then sends inhibitory fibers (GABAergic) to the rostral ventrolateral medulla (RVLM), thus inhibiting the RVLM. The RVLM is the primary regulator of sympathetic nervous system, sending excitatory fibers (catecholaminergic) to the sympathetic preganglionic neurons in the spinal cord. Hence, when the baroreceptors are activated (by an increased blood pressure), the NTS activates the CVLM, which in turn inhibits the RVLM, thus inhibiting the sympathetic branch of the autonomic nervous system leading to a decrease in blood pressure. Likewise, low blood pressure causes an increase in sympathetic tone via "disinhibition" (less inhibition, hence activation) of the RVLM. The NTS also sends excitatory fibers to the Nucleus ambiguus (vagal nuclei) that regulate the parasympathetic nervous system, aiding in the decrease in sympathetic activity during conditions of elevated blood pressure. # Baroreceptor activation The baroreceptors are stretch-sensitive mechanoreceptors. When blood pressure rises, the carotid and aortic sinuses are distended, resulting in stretch and therefore activation of the baroreceptors. Active baroreceptors fire action potentials ("spikes") more frequently than inactive baroreceptors. The greater the stretch, the more rapidly baroreceptors fire action potentials. These action potentials are relayed to the nucleus of the tractus solitarius (NTS), which uses frequency as a measure of blood pressure. As discussed previously, increased activation of the NTS inhibits the vasomotor center and stimulates the vagal nuclei. The end result of baroreceptor activation is inhibition of the sympathetic nervous system and activation of the parasympathetic nervous system. The sympathetic and parasympathetic branches of the autonomic nervous system have opposing effects on blood pressure. Sympathetic activation leads to an elevation of total peripheral resistance and cardiac output via increased contractility of the heart, heart rate, and arterial vasoconstriction, which tends to increase blood pressure. Conversely, parasympathetic activation leads to a decreased cardiac output via decrease in contractility and heart rate, resulting in a tendency to decrease blood pressure. By coupling sympathetic inhibition and parasympathetic activation, the baroreflex maximizes blood pressure reduction. Sympathetic inhibition leads to a drop in peripheral resistance, while parasympathetic activation leads to a depressed heart rate and contractility. The combined effects will dramatically decrease blood pressure. Similarly, sympathetic activation with parasympathetic inhibition allows the baroreflex to elevate blood pressure. CVRx, Inc., a private company located in Minneapolis, Minnesota, has developed an implantable device to treat patients with high blood pressure that cannot be controlled with medications (resistant hypertension) by electrically activating the baroreceptors. This investigational device is called the Rheos Baroreflex Hypertension Therapy System. It is currently under evaluation in an FDA-regulated, phase III clinical trial. # Set point and tonic activation Baroreceptors are active above the baroreceptor set point at mean arterial pressures (MAP) above approximately 70 mm Hg. When MAP falls below the set point, baroreceptors are almost silent. The baroreceptor set point is not fixed; its value may change with changes in blood pressure. For example, in hypertension, the set point will increase; on the other hand, hypotension will result in a depression of the baroreceptor set point. At a MAP below approximately 50 mm Hg, baroreceptors are completely silent. # Effect on heart rate variability The baroreflex may be responsible for a part of the low-frequency component of heart rate variability, the so called Mayer waves, at 0.1 Hz [Sleight, 1995].	https://www.wikidoc.org/index.php/Baroreceptor_reflex
513e86dc38974a1ceddef5adb709284291f9b30b	wikidoc	Bartonella	Bartonella # Overview Bartonella (formerly known as Rochalimaea) is a genus of Gram-negative bacteria. Facultative intracellular parasites, Bartonella species can infect healthy people but are considered especially important as opportunistic pathogens. Bartonella are transmitted by insect vectors such as ticks, fleas, sand flies and mosquitoes. At least eight Bartonella species or subspecies are known to infect humans. In June 2007, a new species under the genus, called Bartonella rochalimae, was discovered. This is the sixth species known to infect humans, and the ninth species and subspecies, overall, known to infect humans. Members of the genus Bartonella are alpha 2 subgroup Proteobacteria. The genus comprises: # Historical Perspective Bartonella species have been infecting humans for thousands of years, as demonstrated by Bartonella quintana DNA in a 4000 year old tooth. The genus is named after Alberto Leonardo Barton Thompson, a Peruvian scientist born in Argentina. Bartonella was found to be a tick borne pathogen in 1999. In 2001 doctors treating Lyme disease first reported that their patients were co-infected with Bartonella. Multiple reports of this finding seem to indicate that Bartonella is not only a tick borne but a tick-transmitted pathogen; however, actual transmission via this route has not yet been proven. # Pathophysiology ## Infection cycle The currently accepted model explaining the infection cycle holds that the transmitting vectors are blood-sucking arthropods and the reservoir hosts are mammals. Immediately after infection, the bacteria colonize a primary niche, the endothelial cells. Every five days, a part of the Bartonella in the endothelial cells are released in the blood stream where they infect erythrocytes. The bacteria then invade and replicate within a phagosomal membrane inside the erythrocytes. Inside the erythrocytes, bacteria multiply until they reach a critical population density. At this point, the Bartonella has simply to wait until it is taken with the erythrocytes by a blood-sucking arthropod. Bartonella infections are remarkable in the wide range of symptoms an infection can produce: the time course (acute or chronic) as well as the underlying pathology are highly variable. ## Medical Treatment - Bartonella - 1. Bartonella quintana - 1.1 Acute or chronic infections without endocarditis - Preferred regimen: Doxycycline 200 mg PO qd or 100 mg bid for 4 weeks AND Gentamicin 3 mg/kg IV qd for the first 2 weeks - 1.2 Endocarditis - Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g IV q24h for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks - 2. Bartonella elizabethae - 2.1 Endocarditis - Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g IV q24h for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks - 3. Bartonella bacilliformis - 3.1 Oroya fever - Preferred regimen: Ciprofloxacin 500 mg PO bid for 14 days - Note: If severe disease, add Ceftriaxone 1 g IV qd for 14 days - 3.2 Verruga peruana - Preferred regimen: Azithromycin 500 mg PO qd for 7 days - Alternative regimen (1): Rifampin 600 mg PO qd for 14-21 days - Alternative regimen (2): Ciprofloxacin 500 mg bid for 7-10 days - 4. Bartonella henselae - 4.1 Cat scratch disease - No treatment recommended for typical cat scratch disease, consider treatment if there is an extensive lymphadenopathy - 4.1.1 If extensive lymphadenopathy - Preferred regimen (1) (pediatrics): Azithromycin 500 mg PO on day 1 THEN 250 mg PO qd on days 2 to 5 - Preferred regimen (2) (adults): Azithromycin 1 g PO at day 1 THEN 500 mg PO for 4 days - 4.2 Endocarditis - Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g/day IV for 6weeks ± Doxycycline 100 mg PO bid for 6 weeks - 4.3 Retinitis - Preferred regimen: Doxycycline 100 mg bid AND Rifampin 300 mg bid PO for 4-6 weeks - 4.4 Bacillary angiomatosis - Preferred regimen (1): Erythromycin 500 mg PO qid for 2 months at least - Preferred regimen (2): Doxycycline 100 mg PO bid for 2 months at least - 4.5 Bacillary Pelliosis - Preferred regimen (1): Erythromycin 500 mg PO qid for 4 months at least - Preferred regimen (2): Doxycycline 100 mg PO bid for 4 months at least	Bartonella Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Faizan Sheraz, M.D. [2] # Overview Bartonella (formerly known as Rochalimaea) is a genus of Gram-negative bacteria. Facultative intracellular parasites, Bartonella species can infect healthy people but are considered especially important as opportunistic pathogens.[1] Bartonella are transmitted by insect vectors such as ticks, fleas, sand flies and mosquitoes. At least eight Bartonella species or subspecies are known to infect humans.[2] In June 2007, a new species under the genus, called Bartonella rochalimae, was discovered.[3] This is the sixth species known to infect humans, and the ninth species and subspecies, overall, known to infect humans. Members of the genus Bartonella are alpha 2 subgroup Proteobacteria. The genus comprises: # Historical Perspective Bartonella species have been infecting humans for thousands of years, as demonstrated by Bartonella quintana DNA in a 4000 year old tooth.[4] The genus is named after Alberto Leonardo Barton Thompson, a Peruvian scientist born in Argentina. Bartonella was found to be a tick borne pathogen in 1999.[5] In 2001 doctors treating Lyme disease first reported that their patients were co-infected with Bartonella.[5] Multiple reports of this finding seem to indicate that Bartonella is not only a tick borne but a tick-transmitted pathogen;[6] however, actual transmission via this route has not yet been proven. # Pathophysiology ## Infection cycle The currently accepted model explaining the infection cycle holds that the transmitting vectors are blood-sucking arthropods and the reservoir hosts are mammals. Immediately after infection, the bacteria colonize a primary niche, the endothelial cells. Every five days, a part of the Bartonella in the endothelial cells are released in the blood stream where they infect erythrocytes. The bacteria then invade and replicate within a phagosomal membrane inside the erythrocytes. Inside the erythrocytes, bacteria multiply until they reach a critical population density. At this point, the Bartonella has simply to wait until it is taken with the erythrocytes by a blood-sucking arthropod. Bartonella infections are remarkable in the wide range of symptoms an infection can produce: the time course (acute or chronic) as well as the underlying pathology are highly variable.[7] ## Medical Treatment - Bartonella[11] - 1. Bartonella quintana - 1.1 Acute or chronic infections without endocarditis[12] - Preferred regimen: Doxycycline 200 mg PO qd or 100 mg bid for 4 weeks AND Gentamicin 3 mg/kg IV qd for the first 2 weeks - 1.2 Endocarditis[13] - Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g IV q24h for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks - 2. Bartonella elizabethae - 2.1 Endocarditis[13] - Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g IV q24h for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks - 3. Bartonella bacilliformis - 3.1 Oroya fever - Preferred regimen: Ciprofloxacin 500 mg PO bid for 14 days - Note: If severe disease, add Ceftriaxone 1 g IV qd for 14 days - 3.2 Verruga peruana[14] - Preferred regimen: Azithromycin 500 mg PO qd for 7 days - Alternative regimen (1): Rifampin 600 mg PO qd for 14-21 days - Alternative regimen (2): Ciprofloxacin 500 mg bid for 7-10 days - 4. Bartonella henselae[15] - 4.1 Cat scratch disease - No treatment recommended for typical cat scratch disease, consider treatment if there is an extensive lymphadenopathy - 4.1.1 If extensive lymphadenopathy - Preferred regimen (1) (pediatrics): Azithromycin 500 mg PO on day 1 THEN 250 mg PO qd on days 2 to 5 - Preferred regimen (2) (adults): Azithromycin 1 g PO at day 1 THEN 500 mg PO for 4 days - 4.2 Endocarditis - Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g/day IV for 6weeks ± Doxycycline 100 mg PO bid for 6 weeks - 4.3 Retinitis - Preferred regimen: Doxycycline 100 mg bid AND Rifampin 300 mg bid PO for 4-6 weeks - 4.4 Bacillary angiomatosis[16] - Preferred regimen (1): Erythromycin 500 mg PO qid for 2 months at least - Preferred regimen (2): Doxycycline 100 mg PO bid for 2 months at least - 4.5 Bacillary Pelliosis[16] - Preferred regimen (1): Erythromycin 500 mg PO qid for 4 months at least - Preferred regimen (2): Doxycycline 100 mg PO bid for 4 months at least	https://www.wikidoc.org/index.php/Bartellona_Infections
7711786f8a8b0efb1bc29522a806f8d19dcd2581	wikidoc	Basal rate	Basal rate In biology, basal rate is the rate of continuous supply of some chemical or process. In the case of diabetes mellitus, it is a low rate of continuous insulin supply needed for such purposes as controlling cellular glucose and amino acid uptake. Together with a bolus of insulin, the basal insulin completes the total insulin needs of an insulin-dependent person. An insulin pump and wristop controller is one way to arrange for a closely controlled basal insulin rate. The slow-release insulins (e.g, Lantus and Levemir) can provide a similar effect.	Basal rate In biology, basal rate is the rate of continuous supply of some chemical or process. In the case of diabetes mellitus, it is a low rate of continuous insulin supply needed for such purposes as controlling cellular glucose and amino acid uptake. Together with a bolus of insulin, the basal insulin completes the total insulin needs of an insulin-dependent person. An insulin pump and wristop controller is one way to arrange for a closely controlled basal insulin rate. The slow-release insulins (e.g, Lantus and Levemir) can provide a similar effect. # External links - Insulin Pump Terminology: Basal Rates Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Basal_rate
85b6917d95bbd500de29f9048d79d9494f2120d2	wikidoc	Basal vein	Basal vein The basal vein is formed at the anterior perforated substance by the union of - (a) a small anterior cerebral vein which accompanies the anterior cerebral artery, - (b) the deep middle cerebral vein (deep Sylvian vein), which receives tributaries from the insula and neighboring gyri, and runs in the lower part of the lateral cerebral fissure, and - (c) the inferior striate veins, which leave the corpus striatum through the anterior perforated substance. The basal vein passes backward around the cerebral peduncle, and ends in the internal cerebral vein (vein of Galen); it receives tributaries from the interpeduncular fossa, the inferior horn of the lateral ventricle, the hippocampal gyrus, and the mid-brain.	Basal vein Template:Infobox Vein Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The basal vein is formed at the anterior perforated substance by the union of - (a) a small anterior cerebral vein which accompanies the anterior cerebral artery, - (b) the deep middle cerebral vein (deep Sylvian vein), which receives tributaries from the insula and neighboring gyri, and runs in the lower part of the lateral cerebral fissure, and - (c) the inferior striate veins, which leave the corpus striatum through the anterior perforated substance. The basal vein passes backward around the cerebral peduncle, and ends in the internal cerebral vein (vein of Galen); it receives tributaries from the interpeduncular fossa, the inferior horn of the lateral ventricle, the hippocampal gyrus, and the mid-brain. # External links - Diagram at ucla.edu Template:Gray's Template:VeinsHeadNeck Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Basal_vein
21d82d10227e477440936646e65fec8597cb935f	wikidoc	Base metal	Base metal In chemistry, the term base metal is used informally to refer to a metal that oxidizes or corrodes relatively easily, and reacts variably with diluted hydrochloric acid (HCl) to form hydrogen. Examples include iron, nickel, lead and zinc. Copper is considered a base metal as it oxidizes relatively easily, although it does not react with HCl. It is commonly used in opposition to noble metal. In alchemy, a base metal was a common and inexpensive metal, as opposed to precious metals, mainly gold and silver. A longtime goal of the alchemists was the transmutation of base metals into precious metals. In numismatics, coins used to derive their value primarily from the precious metal content. Most modern currencies are fiat currency, allowing the coins to be made of base metal. In mining and economics, base metals refers to industrial non-ferrous metals excluding precious metals. These include copper, aluminium, lead, nickel, tin and zinc.	Base metal In chemistry, the term base metal is used informally to refer to a metal that oxidizes or corrodes relatively easily, and reacts variably with diluted hydrochloric acid (HCl) to form hydrogen. Examples include iron, nickel, lead and zinc. Copper is considered a base metal as it oxidizes relatively easily, although it does not react with HCl. It is commonly used in opposition to noble metal. In alchemy, a base metal was a common and inexpensive metal, as opposed to precious metals, mainly gold and silver. A longtime goal of the alchemists was the transmutation of base metals into precious metals. In numismatics, coins used to derive their value primarily from the precious metal content. Most modern currencies are fiat currency, allowing the coins to be made of base metal. In mining and economics, base metals refers to industrial non-ferrous metals excluding precious metals. These include copper, aluminium, lead, nickel, tin and zinc.	https://www.wikidoc.org/index.php/Base_metal
47c833b09134cbe229c73e4df8efcac75282ef96	wikidoc	Sequencing	Sequencing # Overview In genetics and biochemistry, sequencing means to determine the primary structure (or primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which succinctly summarizes much of the atomic-level structure of the sequenced molecule. # DNA sequencing DNA sequencing is the process of determining the nucleotide order of a given DNA fragment. Thus far, most DNA sequencing has been performed using the chain termination method developed by Frederick Sanger. This technique uses sequence-specific termination of a DNA synthesis reaction using modified nucleotide substrates. However, new sequencing technologies such as Pyrosequencing is gaining an increasing share of the sequencing market. Majority of genome data are being produced by Pyrosequencing than Sanger DNA sequencing these days. Pyrosequencing has enabled rapid genome sequencing. Bacterial genome can be sequenced in a single run with several X coverage with this technique. This technique was also used to sequence the genome of James Watson recently. The sequence of DNA encodes the necessary information for living things to survive and reproduce. Determining the sequence is therefore useful in 'pure' research into why and how organisms live, as well as in applied subjects. Because of the key nature of DNA to living things, knowledge of DNA sequence may come in useful in practically any biological research. For example, in medicine it can be used to identify, diagnose and potentially develop treatments for genetic diseases. Similarly, research into pathogens may lead to treatments for contagious diseases. Biotechnology is a burgeoning discipline, with the potential for many useful products and services. ## Sanger sequencing In chain terminator sequencing (Sanger sequencing), extension is initiated at a specific site on the template DNA by using a short oligonucleotide 'primer' complementary to the template at that region. The oligonucleotide primer is extended using a DNA polymerase, an enzyme that replicates DNA. Included with the primer and DNA polymerase are the four deoxynucleotide bases (DNA building blocks), along with a low concentration of a chain terminating nucleotide (most commonly a di-deoxynucleotide). Limited incorporation of the chain terminating nucleotide by the DNA polymerase results in a series of related DNA fragments that are terminated only at positions where that particular nucleotide is used. The fragments are then size-separated by electrophoresis in a slab polyacrylamide gel, or more commonly now, in a narrow glass tube (capillary) filled with a viscous polymer. An alternative to the labelling of the primer is to label the terminators instead, commonly called 'dye terminator sequencing'. The major advantage of this approach is the complete sequencing set can be performed in a single reaction, rather than the four needed with the labeled-primer approach. This is accomplished by labelling each of the dideoxynucleotide chain-terminators with a separate fluorescent dye, which fluoresces at a different wavelength. This method is easier and quicker than the dye primer approach, but may produce more uneven data peaks (different heights), due to a template dependent difference in the incorporation of the large dye chain-terminators. This problem has been significantly reduced with the introduction of new enzymes and dyes that minimize incorporation variability. This method is now used for the vast majority of sequencing reactions as it is both simpler and cheaper. The major reason for this is that the primers do not have to be separately labelled (which can be a significant expense for a single-use custom primer), although this is less of a concern with frequently used 'universal' primers. ## Pyrosequencing Pyrosequencing, which was originally developed by Mostafa Ronaghi, has been commercialized by Biotage (for low throughput sequencing) and 454 Life Sciences (for high-throughput sequencing). The latter platform sequences roughly 100 megabases in a 7-hour run with a single machine. In the array-based method (commercialized by 454 Life Sciences), single-stranded DNA is annealed to beads and amplified via emPCR. These DNA-bound beads are then placed into wells on a fiber-optic chip along with enzymes which produce light in the presence of ATP. When free nucleotides are washed over this chip, light is produced as ATP is generated when nucleotides join with their complementary base pairs. Addition of one (or more) nucleotide(s) results in a reaction that generates a light signal that is recorded by the CCD camera in the instrument. The signal strength is proportional to the number of nucleotides, for example, homopolymer stretches, incorporated in a single nucleotide flow. # RNA sequencing RNA is less stable in the cell, and also more prone to nuclease attack experimentally. As RNA is generated by transcription from DNA, the information is already present in the cell's DNA. However, it is sometimes desirable to sequence RNA molecules. In particular, in Eukaryotes RNA molecules are not necessarily co-linear with their DNA template, as introns are excised. To sequence RNA, the usual method is first to reverse transcribe the sample to generate DNA fragments. This can then be sequenced as described above. # Protein sequencing Methods for performing protein sequencing include: - Edman degradation - Peptide mass fingerprinting - Mass spectrometry If the gene encoding the protein can be identified it is currently much easier to sequence the DNA and infer the protein sequence. Determining part of a protein's amino-acid sequence (often one end) by one of the above methods may be sufficient to enable the identification of a clone carrying the gene. # Polysaccharide sequencing Though polysaccharides are also biopolymers, it is not so common to talk of 'sequencing' a polysaccharide, for several reasons. Although many polysaccharides are linear, many have branches. Many different units (individual monosaccharides) can be used, and bonded in different ways. However, the main theoretical reason is that whereas the other polymers listed here are primarily generated in a 'template-dependent' manner by one processive enzyme, each individual join in a polysaccharide may be formed by a different enzyme. In many cases the assembly is not uniquely specified; depending on which enzyme acts, one of several different units may be incorporated. This can lead to a family of similar molecules being formed. This is particularly true for plant polysaccharides. Methods for the structure determination of oligosaccharides and polysaccharides include NMR spectroscopy and methylation analysis.	Sequencing # Overview In genetics and biochemistry, sequencing means to determine the primary structure (or primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which succinctly summarizes much of the atomic-level structure of the sequenced molecule. # DNA sequencing DNA sequencing is the process of determining the nucleotide order of a given DNA fragment. Thus far, most DNA sequencing has been performed using the chain termination method developed by Frederick Sanger. This technique uses sequence-specific termination of a DNA synthesis reaction using modified nucleotide substrates. However, new sequencing technologies such as Pyrosequencing is gaining an increasing share of the sequencing market. Majority of genome data are being produced by Pyrosequencing than Sanger DNA sequencing these days. Pyrosequencing has enabled rapid genome sequencing. Bacterial genome can be sequenced in a single run with several X coverage with this technique. This technique was also used to sequence the genome of James Watson recently. The sequence of DNA encodes the necessary information for living things to survive and reproduce. Determining the sequence is therefore useful in 'pure' research into why and how organisms live, as well as in applied subjects. Because of the key nature of DNA to living things, knowledge of DNA sequence may come in useful in practically any biological research. For example, in medicine it can be used to identify, diagnose and potentially develop treatments for genetic diseases. Similarly, research into pathogens may lead to treatments for contagious diseases. Biotechnology is a burgeoning discipline, with the potential for many useful products and services. ## Sanger sequencing In chain terminator sequencing (Sanger sequencing), extension is initiated at a specific site on the template DNA by using a short oligonucleotide 'primer' complementary to the template at that region. The oligonucleotide primer is extended using a DNA polymerase, an enzyme that replicates DNA. Included with the primer and DNA polymerase are the four deoxynucleotide bases (DNA building blocks), along with a low concentration of a chain terminating nucleotide (most commonly a di-deoxynucleotide). Limited incorporation of the chain terminating nucleotide by the DNA polymerase results in a series of related DNA fragments that are terminated only at positions where that particular nucleotide is used. The fragments are then size-separated by electrophoresis in a slab polyacrylamide gel, or more commonly now, in a narrow glass tube (capillary) filled with a viscous polymer. An alternative to the labelling of the primer is to label the terminators instead, commonly called 'dye terminator sequencing'. The major advantage of this approach is the complete sequencing set can be performed in a single reaction, rather than the four needed with the labeled-primer approach. This is accomplished by labelling each of the dideoxynucleotide chain-terminators with a separate fluorescent dye, which fluoresces at a different wavelength. This method is easier and quicker than the dye primer approach, but may produce more uneven data peaks (different heights), due to a template dependent difference in the incorporation of the large dye chain-terminators. This problem has been significantly reduced with the introduction of new enzymes and dyes that minimize incorporation variability. This method is now used for the vast majority of sequencing reactions as it is both simpler and cheaper. The major reason for this is that the primers do not have to be separately labelled (which can be a significant expense for a single-use custom primer), although this is less of a concern with frequently used 'universal' primers. ## Pyrosequencing Pyrosequencing, which was originally developed by Mostafa Ronaghi, has been commercialized by Biotage (for low throughput sequencing) and 454 Life Sciences (for high-throughput sequencing). The latter platform sequences roughly 100 megabases in a 7-hour run with a single machine. In the array-based method (commercialized by 454 Life Sciences), single-stranded DNA is annealed to beads and amplified via emPCR. These DNA-bound beads are then placed into wells on a fiber-optic chip along with enzymes which produce light in the presence of ATP. When free nucleotides are washed over this chip, light is produced as ATP is generated when nucleotides join with their complementary base pairs. Addition of one (or more) nucleotide(s) results in a reaction that generates a light signal that is recorded by the CCD camera in the instrument. The signal strength is proportional to the number of nucleotides, for example, homopolymer stretches, incorporated in a single nucleotide flow. [1] # RNA sequencing RNA is less stable in the cell, and also more prone to nuclease attack experimentally. As RNA is generated by transcription from DNA, the information is already present in the cell's DNA. However, it is sometimes desirable to sequence RNA molecules. In particular, in Eukaryotes RNA molecules are not necessarily co-linear with their DNA template, as introns are excised. To sequence RNA, the usual method is first to reverse transcribe the sample to generate DNA fragments. This can then be sequenced as described above. # Protein sequencing Methods for performing protein sequencing include: - Edman degradation - Peptide mass fingerprinting - Mass spectrometry If the gene encoding the protein can be identified it is currently much easier to sequence the DNA and infer the protein sequence. Determining part of a protein's amino-acid sequence (often one end) by one of the above methods may be sufficient to enable the identification of a clone carrying the gene. # Polysaccharide sequencing Though polysaccharides are also biopolymers, it is not so common to talk of 'sequencing' a polysaccharide, for several reasons. Although many polysaccharides are linear, many have branches. Many different units (individual monosaccharides) can be used, and bonded in different ways. However, the main theoretical reason is that whereas the other polymers listed here are primarily generated in a 'template-dependent' manner by one processive enzyme, each individual join in a polysaccharide may be formed by a different enzyme. In many cases the assembly is not uniquely specified; depending on which enzyme acts, one of several different units may be incorporated. This can lead to a family of similar molecules being formed. This is particularly true for plant polysaccharides. Methods for the structure determination of oligosaccharides and polysaccharides include NMR spectroscopy and methylation analysis[1].	https://www.wikidoc.org/index.php/Base_sequence
41c261dc23bfa33b0a5a68d988f3531a003faad4	wikidoc	Basophilia	Basophilia Synonyms and keywords: Basophil count raised (peripheral blood); raised basophil count (peripheral blood) # Overview Basophils are the least seen granulocytes in a peripheral smear and makeup about 0.01% to 0.3% of circulating leukocytes. Basophilia is characterized by an absolute blood basophil count greater than 200cells/μL. Isolated basophilia is infrequently seen as the condition occurs concurrently with other white blood cell disorders such as eosinophilia. # Historical Perspective was first discovered by , a , in /during/following . The association between and was made in/during . In , was the first to discover the association between and the development of . In , mutations were first implicated in the pathogenesis of . There have been several outbreaks of , including -----. In , was developed by to treat/diagnose . # Classification There is no established system for the classification of . OR may be classified according to into subtypes/groups: , , , and . OR may be classified into subtypes based on , , and . may be classified into several subtypes based on , , and . OR Based on the duration of symptoms, may be classified as either acute or chronic. OR If the staging system involves specific and characteristic findings and features: According to the , there are stages of based on the , , and . Each stage is assigned a and a that designate the and . OR The staging of is based on the . OR There is no established system for the staging of . # Pathophysiology The exact pathogenesis of is not fully understood. OR It is thought that is the result of / is mediated by / is produced by / is caused by either , , or . OR is usually transmitted via the route to the human host. OR Following transmission/ingestion, the uses the to invade the cell. OR arises from s, which are cells that are normally involved in . OR The progression to usually involves the . OR The pathophysiology of depends on the histological subtype. # Causes Disease name] may be caused by , , or . OR Common causes of include , , and . OR The most common cause of is . Less common causes of include , , and . OR The cause of has not been identified. To review risk factors for the development of , click here. ## Causes by Organ System ## Causes in Alphabetical Order - Acute hypersensitivity - Basophilic leukaemia - Blastic Acute myeloid leukemia - Chicken pox - Chronic airway disease - Chronic dermatitis - Chronic hemolytic anemia - Chronic myelogenous leukemia - Chronic sinusitis - Congenital hemolytic anemia - Crohn’s disease - Drug hypersensitivity - Estrogens - Extramedullary hematopoiesis - Foreign protein ingestion - Hereditary spherocytosis - Herpes Zoster - Hodgkin's disease - Hookworm disease - Hypothyroidism - Influenza - Ionizing radiation - Iron deficiency - Leukemoid reaction - Lymphoma - Mastocytosis - Minimal change disease - Myelofibrosis - Nephrotic syndrome - Ovulation - Pansinusitis - Polycythemia vera - Small pox - Spleenectomy - Subcutaneous abscess - Subhepatic abscess - Transfusion reaction - Tuberculosis - Ulcerative colitis # Differentiating ((Page name)) from other Diseases must be differentiated from other diseases that cause , , and , such as , , and . OR must be differentiated from , , and . # Epidemiology and Demographics The incidence/prevalence of is approximately per 100,000 individuals worldwide. OR In , the incidence/prevalence of was estimated to be cases per 100,000 individuals worldwide. OR In , the incidence of is approximately per 100,000 individuals with a case-fatality rate of %. Patients of all age groups may develop . OR The incidence of increases with age; the median age at diagnosis is years. OR commonly affects individuals younger than/older than years of age. OR is usually first diagnosed among . OR commonly affects . There is no racial predilection to . OR usually affects individuals of the race. individuals are less likely to develop . affects men and women equally. OR are more commonly affected by than . The to ratio is approximately to 1. The majority of cases are reported in . OR is a common/rare disease that tends to affect and . # Risk Factors There are no established risk factors for . OR The most potent risk factor in the development of is . Other risk factors include , , and . OR Common risk factors in the development of include , , , and . OR Common risk factors in the development of may be occupational, environmental, genetic, and viral. # Screening There is insufficient evidence to recommend routine screening for . OR According to the , screening for is not recommended. OR According to the , screening for by is recommended every among patients with , , and . # Natural History, Complications, and Prognosis If left untreated, % of patients with may progress to develop , , and . OR Common complications of include , , and . OR Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with is approximately %. # Diagnosis ## Diagnostic Study of Choice The diagnosis of is made when at least of the following diagnostic criteria are met: , , , and . OR The diagnosis of is based on the criteria, which include , , and . OR The diagnosis of is based on the definition, which includes , , and . OR There are no established criteria for the diagnosis of . ## History and Symptoms The majority of patients with are asymptomatic. OR The hallmark of is . A positive history of and is suggestive of . The most common symptoms of include , , and . Common symptoms of include , , and . Less common symptoms of include , , and . ## Physical Examination Patients with usually appear . Physical examination of patients with is usually remarkable for , , and . OR Common physical examination findings of include , , and . OR The presence of on physical examination is diagnostic of . OR The presence of on physical examination is highly suggestive of . ## Laboratory Findings An elevated/reduced concentration of serum/blood/urinary/CSF/other is diagnostic of . OR Laboratory findings consistent with the diagnosis of include , , and . OR is usually normal among patients with . OR Some patients with may have elevated/reduced concentration of , which is usually suggestive of . OR There are no diagnostic laboratory findings associated with . ## Electrocardiogram There are no ECG findings associated with . OR An ECG may be helpful in the diagnosis of . Findings on an ECG suggestive of/diagnostic of include , , and . ## X-ray There are no x-ray findings associated with . OR An x-ray may be helpful in the diagnosis of . Findings on an x-ray suggestive of/diagnostic of include , , and . OR There are no x-ray findings associated with . However, an x-ray may be helpful in the diagnosis of complications of , which include , , and . ## Echocardiography or Ultrasound There are no echocardiography/ultrasound findings associated with . OR Echocardiography/ultrasound may be helpful in the diagnosis of . Findings on an echocardiography/ultrasound suggestive of/diagnostic of include , , and . OR There are no echocardiography/ultrasound findings associated with . However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of , which include , , and . ## CT scan There are no CT scan findings associated with . OR CT scan may be helpful in the diagnosis of . Findings on CT scan suggestive of/diagnostic of include , , and . OR There are no CT scan findings associated with . However, a CT scan may be helpful in the diagnosis of complications of , which include , , and . ## MRI There are no MRI findings associated with . OR MRI may be helpful in the diagnosis of . Findings on MRI suggestive of/diagnostic of include , , and . OR There are no MRI findings associated with . However, a MRI may be helpful in the diagnosis of complications of , which include , , and . ## Other Imaging Findings There are no other imaging findings associated with . OR may be helpful in the diagnosis of . Findings on an suggestive of/diagnostic of include , , and . ## Other Diagnostic Studies There are no other diagnostic studies associated with . OR may be helpful in the diagnosis of . Findings suggestive of/diagnostic of include , , and . OR Other diagnostic studies for include , which demonstrates , , and , and , which demonstrates , , and . # Treatment ## Medical Therapy There is no treatment for ; the mainstay of therapy is supportive care. OR Supportive therapy for includes , , and . OR The majority of cases of are self-limited and require only supportive care. OR is a medical emergency and requires prompt treatment. OR The mainstay of treatment for is . OR The optimal therapy for depends on the stage at diagnosis. OR is recommended among all patients who develop . OR Pharmacologic medical therapy is recommended among patients with , , and . OR Pharmacologic medical therapies for include (either) , , and/or . OR Empiric therapy for depends on and . OR Patients with are treated with , whereas patients with are treated with . ## Surgery Surgical intervention is not recommended for the management of . OR Surgery is not the first-line treatment option for patients with . Surgery is usually reserved for patients with either , , and OR The mainstay of treatment for is medical therapy. Surgery is usually reserved for patients with either , , and/or . OR The feasibility of surgery depends on the stage of at diagnosis. OR Surgery is the mainstay of treatment for . ## Primary Prevention There are no established measures for the primary prevention of . OR There are no available vaccines against . OR Effective measures for the primary prevention of include , , and . OR vaccine is recommended for to prevent . Other primary prevention strategies include , , and . ## Secondary Prevention There are no established measures for the secondary prevention of . OR Effective measures for the secondary prevention of include , , and .	Basophilia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aisha Adigun, B.Sc., M.D.[2] Synonyms and keywords: Basophil count raised (peripheral blood); raised basophil count (peripheral blood) # Overview Basophils are the least seen granulocytes in a peripheral smear and makeup about 0.01% to 0.3% of circulating leukocytes. Basophilia is characterized by an absolute blood basophil count greater than 200cells/μL. Isolated basophilia is infrequently seen as the condition occurs concurrently with other white blood cell disorders such as eosinophilia. # Historical Perspective [Disease name] was first discovered by [name of scientist], a [nationality + occupation], in [year]/during/following [event]. The association between [important risk factor/cause] and [disease name] was made in/during [year/event]. In [year], [scientist] was the first to discover the association between [risk factor] and the development of [disease name]. In [year], [gene] mutations were first implicated in the pathogenesis of [disease name]. There have been several outbreaks of [disease name], including -----. In [year], [diagnostic test/therapy] was developed by [scientist] to treat/diagnose [disease name]. # Classification There is no established system for the classification of [disease name]. OR [Disease name] may be classified according to [classification method] into [number] subtypes/groups: [group1], [group2], [group3], and [group4]. OR [Disease name] may be classified into [large number > 6] subtypes based on [classification method 1], [classification method 2], and [classification method 3]. [Disease name] may be classified into several subtypes based on [classification method 1], [classification method 2], and [classification method 3]. OR Based on the duration of symptoms, [disease name] may be classified as either acute or chronic. OR If the staging system involves specific and characteristic findings and features: According to the [staging system + reference], there are [number] stages of [malignancy name] based on the [finding1], [finding2], and [finding3]. Each stage is assigned a [letter/number1] and a [letter/number2] that designate the [feature1] and [feature2]. OR The staging of [malignancy name] is based on the [staging system]. OR There is no established system for the staging of [malignancy name]. # Pathophysiology The exact pathogenesis of [disease name] is not fully understood. OR It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3]. OR [Pathogen name] is usually transmitted via the [transmission route] route to the human host. OR Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell. OR [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells]. OR The progression to [disease name] usually involves the [molecular pathway]. OR The pathophysiology of [disease/malignancy] depends on the histological subtype. # Causes Disease name] may be caused by [cause1], [cause2], or [cause3]. OR Common causes of [disease] include [cause1], [cause2], and [cause3]. OR The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4]. OR The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click here. ## Causes by Organ System ## Causes in Alphabetical Order - Acute hypersensitivity - Basophilic leukaemia - Blastic Acute myeloid leukemia - Chicken pox - Chronic airway disease - Chronic dermatitis - Chronic hemolytic anemia - Chronic myelogenous leukemia - Chronic sinusitis - Congenital hemolytic anemia - Crohn’s disease - Drug hypersensitivity - Estrogens - Extramedullary hematopoiesis - Foreign protein ingestion - Hereditary spherocytosis - Herpes Zoster - Hodgkin's disease - Hookworm disease - Hypothyroidism - Influenza - Ionizing radiation - Iron deficiency - Leukemoid reaction - Lymphoma - Mastocytosis - Minimal change disease - Myelofibrosis - Nephrotic syndrome - Ovulation - Pansinusitis - Polycythemia vera - Small pox - Spleenectomy - Subcutaneous abscess - Subhepatic abscess - Transfusion reaction - Tuberculosis - Ulcerative colitis # Differentiating ((Page name)) from other Diseases [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3]. OR [Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3]. # Epidemiology and Demographics The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide. OR In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide. OR In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%. Patients of all age groups may develop [disease name]. OR The incidence of [disease name] increases with age; the median age at diagnosis is [#] years. OR [Disease name] commonly affects individuals younger than/older than [number of years] years of age. OR [Chronic disease name] is usually first diagnosed among [age group]. OR [Acute disease name] commonly affects [age group]. There is no racial predilection to [disease name]. OR [Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name]. [Disease name] affects men and women equally. OR [Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1. The majority of [disease name] cases are reported in [geographical region]. OR [Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2]. # Risk Factors There are no established risk factors for [disease name]. OR The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4]. OR Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4]. OR Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral. # Screening There is insufficient evidence to recommend routine screening for [disease/malignancy]. OR According to the [guideline name], screening for [disease name] is not recommended. OR According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3]. # Natural History, Complications, and Prognosis If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3]. OR Common complications of [disease name] include [complication 1], [complication 2], and [complication 3]. OR Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%. # Diagnosis ## Diagnostic Study of Choice The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4]. OR The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3]. OR The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3]. OR There are no established criteria for the diagnosis of [disease name]. ## History and Symptoms The majority of patients with [disease name] are asymptomatic. OR The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. ## Physical Examination Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3]. OR Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3]. OR The presence of [finding(s)] on physical examination is diagnostic of [disease name]. OR The presence of [finding(s)] on physical examination is highly suggestive of [disease name]. ## Laboratory Findings An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name]. OR Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3]. OR [Test] is usually normal among patients with [disease name]. OR Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication]. OR There are no diagnostic laboratory findings associated with [disease name]. ## Electrocardiogram There are no ECG findings associated with [disease name]. OR An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. ## X-ray There are no x-ray findings associated with [disease name]. OR An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3]. ## Echocardiography or Ultrasound There are no echocardiography/ultrasound findings associated with [disease name]. OR Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3]. ## CT scan There are no CT scan findings associated with [disease name]. OR [Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3]. ## MRI There are no MRI findings associated with [disease name]. OR [Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3]. ## Other Imaging Findings There are no other imaging findings associated with [disease name]. OR [Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. ## Other Diagnostic Studies There are no other diagnostic studies associated with [disease name]. OR [Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3]. OR Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3]. # Treatment ## Medical Therapy There is no treatment for [disease name]; the mainstay of therapy is supportive care. OR Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3]. OR The majority of cases of [disease name] are self-limited and require only supportive care. OR [Disease name] is a medical emergency and requires prompt treatment. OR The mainstay of treatment for [disease name] is [therapy]. OR The optimal therapy for [malignancy name] depends on the stage at diagnosis. OR [Therapy] is recommended among all patients who develop [disease name]. OR Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3]. OR Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3]. OR Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2]. OR Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2]. ## Surgery Surgical intervention is not recommended for the management of [disease name]. OR Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3] OR The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3]. OR The feasibility of surgery depends on the stage of [malignancy] at diagnosis. OR Surgery is the mainstay of treatment for [disease or malignancy]. ## Primary Prevention There are no established measures for the primary prevention of [disease name]. OR There are no available vaccines against [disease name]. OR Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3]. OR [Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3]. ## Secondary Prevention There are no established measures for the secondary prevention of [disease name]. OR Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].	https://www.wikidoc.org/index.php/Basophil_count_raised_(peripheral_blood)
df7d69c9f1939bc150a6148a72ba001115e76197	wikidoc	Basophilic	Basophilic Basophilic is a technical term used by histologists. It describes the microscopic appearance of cells and tissues, as seen down the microscope, after a histological section has been stained with a basic dye. The most common such dye is haematoxylin. Basophilic describes the appearance of structures seen in histological sections which take up basic dyes. The structures usually stained are those that contain nucleic acid such as the cell nucleus and ribosomes. Basophils are cells that "love" base, and which usually show up deep blue under standard staining techniques (H&E). Specifically, this term refers to: - basophil granulocytes - anterior pituitary basophils	Basophilic Basophilic is a technical term used by histologists. It describes the microscopic appearance of cells and tissues, as seen down the microscope, after a histological section has been stained with a basic dye. The most common such dye is haematoxylin. Basophilic describes the appearance of structures seen in histological sections which take up basic dyes. The structures usually stained are those that contain nucleic acid such as the cell nucleus and ribosomes. Basophils are cells that "love" base, and which usually show up deep blue under standard staining techniques (H&E). Specifically, this term refers to: - basophil granulocytes - anterior pituitary basophils	https://www.wikidoc.org/index.php/Basophilic
368effde4a981547c754317170dda38c04c18a51	wikidoc	Leukopenia	Leukopenia Synonyms and keywords: Deficiency in WBC, deficiency in white blood cells, deficiency in leukocytes, low WBC, low white blood cells, low leukocytes, neutrophilic leukopenia, neutrophilic leukocytopenia, neutrophilic leucopenia, neutrophilic leucocytopenia, neutropenia, eosinophilic leukopenia, eosinophilic leukocytopenia, eosinophilic leucopenia, eosinophilic leucocytopenia, eosinophilopenia, basophilic leukopenia, basophilic leukocytopenia, basophilic leucopenia, basophilic leucocytopenia, basophilopenia, leukocytopenia, leucopenia, leukopaenia, lymphopenia, lymphocytopenia # Overview Deficiency of absolute number of leukocytes, which may be granulocytes (neutrophils, eosinophils, basophils) or lymphocytes (T-cells, B-cells). The majority of cases of leukopenia are actually neutropenia since neutrophils constitute the majority of leukocytes. As the principal function of white cells is to combat infection, a decrease in the number of these cells can place patients at increased risk for infection. In pancytopenia, the other cell types in the blood (red blood cells and platelets) are similarly affected. Neutropenia is a decrease in the number of circulating neutrophil granulocytes, the most abundant white blood cells. The terms leukopenia and neutropenia may occasionally be used interchangeably, as the neutrophil count is the most important indicator of infection risk. However, neutropenia is more properly considered a subset of leukopenia as a whole. Low white cell counts are associated with chemotherapy, radiation therapy, leukemia (as malignant cells overwhelm the bone marrow), myelofibrosis and aplastic anemia (failure of white and red cell creation, along with poor platelet production). In addition, many common medications can cause leukopenia. Other causes of low white blood cell count include: Influenza, systemic lupus erythematosus, typhus, malaria, HIV, tuberculosis, dengue, Rickettsial infections, enlargement of the spleen, folate deficiencies and sepsis. Many other causes exist. Leukopenia can be identified with a complete blood count. # Classification # Causes ## Causes by Organ System ## Causes in Alphabetical Order - Acute cholinergic dysautonomia - Aflibercept - Alcoholism - Alimemazine - Altretamine - Aminosalicylic acid - Amoxicillin - Aplastic anemia - Autoimmune diseases - Azacitidine - Banti syndrome - Benign familial neutropenia - Benzene - Bone marrow damage - Brucellosis - Bullis fever syndrome - Cachexia - Capreomycin sulfate - Carboplatin - Cefaclor - Cefotaxime sodium - Cefpodoxime - Ceftazidime - Certolizumab pegol - Chemotherapy - Chickenpox - Chlorpropamide - Chromosome 8, mosaic trisomy - Cisplatin - Clobazam - Cyclic neutropenia - Cyclophosphamide - Cytarabine - Dacarbazine - Dactinomycin - Degenerative and inflammatory vasculopathies - Dexrazoxane - Diethylpropion - Diphtheria - Diuretics - Docetaxel - Doxorubicin hydrochloride - Drug-induced granulocytopenias - Ehrlichia ewingii - Epirubicin hydrochloride - Epstein-barr virus - Ethosuximide - Exanthema subitum - Fanconi pancytopenia - Febuxostat - Felbamate - Felty syndrome - Flavoxate - Flurazepam hydrochloride - Flurbiprofen - Folate malabsorption, hereditary - Folic acid deficiency - Foscarnet sodium - Fulvestrant - Gaucher disease type 3 - Gemifloxacin mesylate - Ghosal syndrome - Guanidine - Haemodialysis - Heartland virus - Heavy-chain diseases - Herbal agent overdose - Hiv - Homologous wasting disease - Hydroxychloroquine - Hyperdibasic aminoaciduria type 2 - Hyperglobulia - Hypersplenism - Hypopituitarism - Hypothyroidism - Idiopathic - Ifosfamide - Infection - Infectious mononucleosis - Infectious hepatitis - Influenza - Interleukin 2 - Irinotecan hydrochloride - Iron deficiency anemia - Junin virus - Kala-azar - Korovnikov syndrome - Kostmann syndrome - Leishmaniasis - Lenalidomide - Leukemia - Lincomycin hydrochloride - Lipid storage disease - Liver disease - Lomustine - Lorcaserin - Loxapine - Lupus - Lymphocytopenia - Malaria - Malignant lymphomas - Mastocytosis - Mayapple poisoning - Megaloblastic anemia - Megestrol - Melphalan - Mercaptopurine - Meropenem - Metaxalone - Methocarbamol - Methylmalonic acidemia - Milnacipran hydrochloride - Mitomycin c - Monosodium methanarsenate - Mycophenolate - Myelodysplasia - Myeloproliferative disorders - Nabilone - Neutropenia - Nilutamide - Nitisinone - Nitrous oxide - Nutrition deficiency - O'higgins disease - Olanzapine - Olaparib - Olsalazine - Ornithosis - Osteomyelosclerosis - Oxaprozin - Oxazepam - Oxcarbazepine - Paclitaxel - Palbociclib - Paraproteinemia - Paratyphus - Parvovirus b19 - Penicillamine - Pergolide - Pernicious anemia - Perphenazine - Pertuzumab - Poliomyelitis - Pramipexole - Primaquine phosphate - Primary and secondary varicosis - Probenecid - Promethazine - Pyridoxamine 5-prime-phosphate oxidase deficiency - Pyrimethamine - Rabeprazole - Radiotherapy - Radium chloride - Refractory anaemia with ringed sideroblasts - Repaglinide - Rheumatoid arthritis - Rickettsial infection - Rifampin - Romidepsin - Rufinamide - Sabia virus - Sars - Septicaemia - Sirolimus - Sjogren's syndrome - Spironolactone - Spleen disease - Streptozocin - Strontium chloride - Sulindac - Systemic lupus erythematosus - Tamoxifen - Teniposide - Thioguanine - Thiotepa - Thiothixene - Thyrotoxicosis - Tiagabine - Tick borne encephalitis - Tolazamide - Tolbutamide - Toremifene - Toxoplasmosis - Trimethadione - Trisomy 8 mosaicism - Tuberculosis - Tularemia - Tumor infiltration - Typhoid fever - Valganciclovir hydrochloride - Varicella - Vein compression syndrome - Vinblastine - Visceral leishmaniasis - Vitamin b12 deficiency - Yellow fever - Zonisamide # Contraindicated Medications Leukopenia is considered an absolute contraindication to the use of the following medications: - Methotrexate	Leukopenia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] Luke Rusowicz-Orazem, B.S. Synonyms and keywords: Deficiency in WBC, deficiency in white blood cells, deficiency in leukocytes, low WBC, low white blood cells, low leukocytes, neutrophilic leukopenia, neutrophilic leukocytopenia, neutrophilic leucopenia, neutrophilic leucocytopenia, neutropenia, eosinophilic leukopenia, eosinophilic leukocytopenia, eosinophilic leucopenia, eosinophilic leucocytopenia, eosinophilopenia, basophilic leukopenia, basophilic leukocytopenia, basophilic leucopenia, basophilic leucocytopenia, basophilopenia, leukocytopenia, leucopenia, leukopaenia, lymphopenia, lymphocytopenia # Overview Deficiency of absolute number of leukocytes, which may be granulocytes (neutrophils, eosinophils, basophils) or lymphocytes (T-cells, B-cells). The majority of cases of leukopenia are actually neutropenia since neutrophils constitute the majority of leukocytes. As the principal function of white cells is to combat infection, a decrease in the number of these cells can place patients at increased risk for infection. In pancytopenia, the other cell types in the blood (red blood cells and platelets) are similarly affected. Neutropenia is a decrease in the number of circulating neutrophil granulocytes, the most abundant white blood cells. The terms leukopenia and neutropenia may occasionally be used interchangeably, as the neutrophil count is the most important indicator of infection risk. However, neutropenia is more properly considered a subset of leukopenia as a whole. Low white cell counts are associated with chemotherapy, radiation therapy, leukemia (as malignant cells overwhelm the bone marrow), myelofibrosis and aplastic anemia (failure of white and red cell creation, along with poor platelet production). In addition, many common medications can cause leukopenia. Other causes of low white blood cell count include: Influenza, systemic lupus erythematosus, typhus, malaria, HIV, tuberculosis, dengue, Rickettsial infections, enlargement of the spleen, folate deficiencies and sepsis. Many other causes exist. Leukopenia can be identified with a complete blood count. # Classification # Causes ## Causes by Organ System ## Causes in Alphabetical Order - Acute cholinergic dysautonomia - Aflibercept - Alcoholism - Alimemazine - Altretamine - Aminosalicylic acid - Amoxicillin - Aplastic anemia - Autoimmune diseases - Azacitidine - Banti syndrome - Benign familial neutropenia - Benzene - Bone marrow damage - Brucellosis - Bullis fever syndrome - Cachexia - Capreomycin sulfate - Carboplatin - Cefaclor - Cefotaxime sodium - Cefpodoxime - Ceftazidime - Certolizumab pegol - Chemotherapy - Chickenpox - Chlorpropamide - Chromosome 8, mosaic trisomy - Cisplatin - Clobazam - Cyclic neutropenia - Cyclophosphamide - Cytarabine - Dacarbazine - Dactinomycin - Degenerative and inflammatory vasculopathies - Dexrazoxane - Diethylpropion - Diphtheria - Diuretics - Docetaxel - Doxorubicin hydrochloride - Drug-induced granulocytopenias - Ehrlichia ewingii - Epirubicin hydrochloride - Epstein-barr virus - Ethosuximide - Exanthema subitum - Fanconi pancytopenia - Febuxostat - Felbamate - Felty syndrome - Flavoxate - Flurazepam hydrochloride - Flurbiprofen - Folate malabsorption, hereditary - Folic acid deficiency - Foscarnet sodium - Fulvestrant - Gaucher disease type 3 - Gemifloxacin mesylate - Ghosal syndrome - Guanidine - Haemodialysis - Heartland virus - Heavy-chain diseases - Herbal agent overdose - Hiv - Homologous wasting disease - Hydroxychloroquine - Hyperdibasic aminoaciduria type 2 - Hyperglobulia - Hypersplenism - Hypopituitarism - Hypothyroidism - Idiopathic - Ifosfamide - Infection - Infectious mononucleosis - Infectious hepatitis - Influenza - Interleukin 2 - Irinotecan hydrochloride - Iron deficiency anemia - Junin virus - Kala-azar - Korovnikov syndrome - Kostmann syndrome - Leishmaniasis - Lenalidomide - Leukemia - Lincomycin hydrochloride - Lipid storage disease - Liver disease - Lomustine - Lorcaserin - Loxapine - Lupus - Lymphocytopenia - Malaria - Malignant lymphomas - Mastocytosis - Mayapple poisoning - Megaloblastic anemia - Megestrol - Melphalan - Mercaptopurine - Meropenem - Metaxalone - Methocarbamol - Methylmalonic acidemia - Milnacipran hydrochloride - Mitomycin c - Monosodium methanarsenate - Mycophenolate - Myelodysplasia - Myeloproliferative disorders - Nabilone - Neutropenia - Nilutamide - Nitisinone - Nitrous oxide - Nutrition deficiency - O'higgins disease - Olanzapine - Olaparib - Olsalazine - Ornithosis - Osteomyelosclerosis - Oxaprozin - Oxazepam - Oxcarbazepine - Paclitaxel - Palbociclib - Paraproteinemia - Paratyphus - Parvovirus b19 - Penicillamine - Pergolide - Pernicious anemia - Perphenazine - Pertuzumab - Poliomyelitis - Pramipexole - Primaquine phosphate - Primary and secondary varicosis - Probenecid - Promethazine - Pyridoxamine 5-prime-phosphate oxidase deficiency - Pyrimethamine - Rabeprazole - Radiotherapy - Radium chloride - Refractory anaemia with ringed sideroblasts - Repaglinide - Rheumatoid arthritis - Rickettsial infection - Rifampin - Romidepsin - Rufinamide - Sabia virus - Sars - Septicaemia - Sirolimus - Sjogren's syndrome - Spironolactone - Spleen disease - Streptozocin - Strontium chloride - Sulindac - Systemic lupus erythematosus - Tamoxifen - Teniposide - Thioguanine - Thiotepa - Thiothixene - Thyrotoxicosis - Tiagabine - Tick borne encephalitis - Tolazamide - Tolbutamide - Toremifene - Toxoplasmosis - Trimethadione - Trisomy 8 mosaicism - Tuberculosis - Tularemia - Tumor infiltration - Typhoid fever - Valganciclovir hydrochloride - Varicella - Vein compression syndrome - Vinblastine - Visceral leishmaniasis - Vitamin b12 deficiency - Yellow fever - Zonisamide # Contraindicated Medications Leukopenia is considered an absolute contraindication to the use of the following medications: - Methotrexate	https://www.wikidoc.org/index.php/Basophilic_leucocytopenia
bb5f91cab962afe0e607452c186f181cf174caa2	wikidoc	Normoblast	Normoblast # Overview An erythroblast is a type of red blood cell which still retains a cell nucleus. It is the immediate precursor of a normal erythrocyte. # Nomenclature The term normoblast is sometimes used as a synonym for erythroblast, but at other times it is considered a subcategory. In the latter context, there are two types of erythroblasts: - "normoblasts" - develop as expected - "megaloblasts" - an unusually large erythroblast that can be associated with pernicious anemia and folic acid deficiency (collectively called megaloblastic anemia) # Development There are four stages in the development of a normoblast. # Additional images - Blood cell lineage - Hematopoiesis - Blood: Schistocytes: Micro blood film shows an excellent example with normoblast.	Normoblast Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An erythroblast is a type of red blood cell which still retains a cell nucleus. It is the immediate precursor of a normal erythrocyte. # Nomenclature The term normoblast is sometimes used as a synonym for erythroblast, but at other times it is considered a subcategory. In the latter context, there are two types of erythroblasts: - "normoblasts" - develop as expected - "megaloblasts" - an unusually large erythroblast that can be associated with pernicious anemia and folic acid deficiency (collectively called megaloblastic anemia) # Development There are four stages in the development of a normoblast. # Additional images - Blood cell lineage - Hematopoiesis - Blood: Schistocytes: Micro blood film shows an excellent example with normoblast.	https://www.wikidoc.org/index.php/Basophilic_normoblast
16e275330ab718f3d0d5135fa092db3715ca36ba	wikidoc	Bath salts	Bath salts # Overview The name bath salts is applied to a range of soluble, usually inorganic solid products designed to be added to a bath, either to improve cleaning, provide a medical improvement, to improve the experience of bathing, or to serve as a vehicle for cosmetic agents. Such salts include: - magnesium sulfate (Epsom salts) - sodium chloride (table salt) - sodium bicarbonate (baking soda) - sodium hexametaphosphate (Calgon, amorphous/glassy sodium metaphosphate) - sodium sesquicarbonate - borax Although many organic substances commonly used in or with bath water are salts (such as soap and many other surfactants), these are not usually called "bath salts". However, this does not rule out the possibility of low formula weight organic salts such as sodium citrate being called bath salts. As with the naming of other additives, mixed preparations consisting largely though not entirely of salts as described herein may be called "bath salts". Commonest additions are fragrances and colors, and one purpose (in some products the most important one) of salts is as a vehicle or diluent to "stretch" fragrances, which are otherwise often too potent for convenient measurement or use. Other common additives to bath salts are oils (agglomerating the salts, the product being called "bath beads" or "bath oil beads"), foaming agents, and fizzing (effervescent) agents. The appearance of the product before use is sometimes valued, and although bath salts are often packaged for retail in windowless boxes or bags, they may also be displayed in transparent containers. For instance, the needlelike appearance of sodium sesquicarbonate crystals makes them attractive for such purpose. However, bath salts may also be prepared as amorphous granules rather than crystals. # Effects of bath salts Epsom salt is the most tested and has many effects on the muscles and nervous system. Bath salts provide a variety of benefits to a bather. Salts change the osmotic balance of the water so that fewer salts are leeched from the skin via osmosis. This reduces the "pruning" or "wrinkling" effect of prolonged exposure of skin to fresh water. Magnesium sulphate has been shown to be absorbed through the skin, and magnesium has an anti-inflammatory effect. Some bath salts such as phosphates have a detergent action which softens calloused skin and aids in exfoliation. Some bath salts act as water softeners and change the way soap behaves and rinses. High concentrations of salts increase the specific gravity of the water and increase buoyancy which makes the body feel lighter in the bath. Very high concentrations of salts in water are used in flotation therapy. Bath salts are often used to mimic the properties of natural mineral baths or hot springs # Abuse According to a recent study, Bath salts abuse is becoming common, and patients with PABS overdoses are presenting to emergency departments with increasing frequency. The primary ingredient of the synthetic designer drugs in these bath salts, which are not related to any hygiene product, is methylenedioxypyrovalerone (MDPV). MDPV is structurally related to pyrovalerone and α-pyrrolidinophenone compounds that inhibit norepinephrine–dopamine reuptake and thus act as central nervous system stimulants. ## Effect The sympathetic effects may include - tachycardia. - hypertension, - hyperthermia, and - seizures, - deaths have also been reported. Altered mental status presents as - severe panic attacks, - agitation, - paranoia, - hallucinations, and - violent behavior (e.g., self-mutilation, - suicide attempts, - homicidal activity. Thus Psychoactive Bath Salts (PABS) have been described as possessing the worst characteristics of - lysergic acid diethylamide (LSD), - phencyclidine (PCP, or angel dust), - methylenedioxymethamphetamine (ecstasy), - cocaine, and - methamphetamine. ## Treatment It is mainly supportive, typically with: - intravenous benzodiazepines (for sedation, to control seizures, or both) and - intravenous fluids, incase of suspicion of rhabdomyolysis. ## Special Precautions Physicians need to be aware of several issues, which are as follows - Intensive care unit care, because of the severity and potential lethality which can result from overdoses. - Specific drug screen, as routine drug screens do not detect PABS. - Differentiating PABS from other psychoactive substance abuse, which can confound the clinical presentation. - Need of physical restraints and high dose sedatives to prevent self harm and harm to others.	Bath salts Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The name bath salts is applied to a range of soluble, usually inorganic solid products designed to be added to a bath, either to improve cleaning, provide a medical improvement, to improve the experience of bathing, or to serve as a vehicle for cosmetic agents. Such salts include: - magnesium sulfate (Epsom salts) - sodium chloride (table salt) - sodium bicarbonate (baking soda) - sodium hexametaphosphate (Calgon, amorphous/glassy sodium metaphosphate) - sodium sesquicarbonate - borax Although many organic substances commonly used in or with bath water are salts (such as soap and many other surfactants), these are not usually called "bath salts". However, this does not rule out the possibility of low formula weight organic salts such as sodium citrate being called bath salts. As with the naming of other additives, mixed preparations consisting largely though not entirely of salts as described herein may be called "bath salts". Commonest additions are fragrances and colors, and one purpose (in some products the most important one) of salts is as a vehicle or diluent to "stretch" fragrances, which are otherwise often too potent for convenient measurement or use. Other common additives to bath salts are oils (agglomerating the salts, the product being called "bath beads" or "bath oil beads"), foaming agents, and fizzing (effervescent) agents. The appearance of the product before use is sometimes valued, and although bath salts are often packaged for retail in windowless boxes or bags, they may also be displayed in transparent containers. For instance, the needlelike appearance of sodium sesquicarbonate crystals makes them attractive for such purpose. However, bath salts may also be prepared as amorphous granules rather than crystals. # Effects of bath salts Epsom salt is the most tested and has many effects on the muscles and nervous system. Bath salts provide a variety of benefits to a bather. Salts change the osmotic balance of the water so that fewer salts are leeched from the skin via osmosis. This reduces the "pruning" or "wrinkling" effect of prolonged exposure of skin to fresh water. Magnesium sulphate has been shown to be absorbed through the skin, and magnesium has an anti-inflammatory effect. Some bath salts such as phosphates have a detergent action which softens calloused skin and aids in exfoliation. Some bath salts act as water softeners and change the way soap behaves and rinses. High concentrations of salts increase the specific gravity of the water and increase buoyancy which makes the body feel lighter in the bath. Very high concentrations of salts in water are used in flotation therapy. Bath salts are often used to mimic the properties of natural mineral baths or hot springs # Abuse According to a recent study, Bath salts abuse is becoming common, and patients with PABS overdoses are presenting to emergency departments with increasing frequency. The primary ingredient of the synthetic designer drugs in these bath salts, which are not related to any hygiene product, is methylenedioxypyrovalerone (MDPV). MDPV is structurally related to pyrovalerone and α-pyrrolidinophenone compounds that inhibit norepinephrine–dopamine reuptake and thus act as central nervous system stimulants. ## Effect The sympathetic effects may include - tachycardia. - hypertension, - hyperthermia, and - seizures, - deaths have also been reported. Altered mental status presents as - severe panic attacks, - agitation, - paranoia, - hallucinations, and - violent behavior (e.g., self-mutilation, - suicide attempts, - homicidal activity. Thus Psychoactive Bath Salts (PABS) have been described as possessing the worst characteristics of - lysergic acid diethylamide (LSD), - phencyclidine (PCP, or angel dust), - methylenedioxymethamphetamine (ecstasy), - cocaine, and - methamphetamine. ## Treatment It is mainly supportive, typically with: - intravenous benzodiazepines (for sedation, to control seizures, or both) and - intravenous fluids, incase of suspicion of rhabdomyolysis. ## Special Precautions Physicians need to be aware of several issues, which are as follows - Intensive care unit care, because of the severity and potential lethality which can result from overdoses. - Specific drug screen, as routine drug screens do not detect PABS. - Differentiating PABS from other psychoactive substance abuse, which can confound the clinical presentation. - Need of physical restraints and high dose sedatives to prevent self harm and harm to others. # External links http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6019a6.htm Template:WH Template:WikiDoc Sources Bold text	https://www.wikidoc.org/index.php/Bath_salts
8705f43d3d3b6ba8bec31cdf4977c68b936d0214	wikidoc	Bay Laurel	Bay Laurel The Bay Laurel (Laurus nobilis, Lauraceae), also known as True Laurel, Sweet Bay, Grecian Laurel, Laurel, or Bay Tree, is an aromatic evergreen tree or large shrub reaching 10–18 m tall, native to the Mediterranean region. The leaves are 6–12 cm long and 2–4 cm broad, with a characteristic finely serrated and wrinkled margin. It is dioecious, with male and female flowers on separate plants; each flower is pale yellow-green, about 1 cm diameter, borne in pairs together beside a leaf. The fruit is a small black berry about 1 cm long, containing a single seed. # Uses and symbolism Bay Laurel is the source of the bay leaves which are used for their flavour in cooking. It was also the source of the laurel wreath of ancient Greece, and therefore the expression of "resting on one's laurels". A wreath of bay laurels was given as the prize at the Pythian Games because the games were in honor of Apollo and the laurel was one of his symbols ever since his unsuccessful pursuit of Daphne. In the Bible, the sweet-bay is often an emblem of prosperity and fame. In Christianity it is said to symbolize the Resurrection of Christ and the triumph of Humanity thereby. It is also the source of the word baccalaureate (laurel berry), and of poet laureate. Some evidence from the medical literature supports Bay Laurel having these uses: - Antioxidative: Fitoterapia. 2003 Sep;74(6):613-6. - Analgesic and anti-inflammatory: Phytother Res. 2003 Aug;17(7):733-6. - Anticonvulsant (antiepileptic): Phytomedicine. 2002 Apr;9(3):212-6. In Chinese folklore there is a great laurel tree on the moon, and the Chinese name for the laurel, 月桂, literally translates to "moon-laurel". This is the subject of a story of Wu Gang, a man who aspired to immortality and neglected his work. When the deities discovered this they sentenced Wu Gang to fell the laurel tree, whereupon he could join the ranks of the deities; however, since the laurel regenerated immediately when cut, it could never be felled. The phrase 吴刚伐木 ("Wu Gang felling the tree") is sometimes used to refer to endless toil, analogous to Sisyphus in Greek mythology. It is also widely cultivated as an ornamental plant in regions with mediterranean or oceanic climates, and as an indoor plant in colder regions. Bay leaves are eaten by the caterpillars of some Lepidoptera, for example the Eastern tiger swallowtail (Papilio glaucus). - Bay Laurel grown in a kitchen for bay leaves Bay Laurel grown in a kitchen for bay leaves - 19th century illustration 19th century illustration # Trivia - Bay laurel leaves are used in the design of the 10 yen coin in Japan. - In Greek mythology, the tree was first formed when the nymph Daphne changed into it to escape the lustful pursuit of the Olympian god Apollo; see Apollo and Daphne. Daphne is the Greek name for the tree. - The National Emblem of Greece consists of a blue escutcheon with a white cross totally surrounded by two laurel branches.	Bay Laurel The Bay Laurel (Laurus nobilis, Lauraceae), also known as True Laurel, Sweet Bay, Grecian Laurel, Laurel, or Bay Tree, is an aromatic evergreen tree or large shrub reaching 10–18 m tall, native to the Mediterranean region. The leaves are 6–12 cm long and 2–4 cm broad, with a characteristic finely serrated and wrinkled margin. It is dioecious, with male and female flowers on separate plants; each flower is pale yellow-green, about 1 cm diameter, borne in pairs together beside a leaf. The fruit is a small black berry about 1 cm long, containing a single seed. # Uses and symbolism Bay Laurel is the source of the bay leaves which are used for their flavour in cooking. It was also the source of the laurel wreath of ancient Greece, and therefore the expression of "resting on one's laurels". A wreath of bay laurels was given as the prize at the Pythian Games because the games were in honor of Apollo and the laurel was one of his symbols ever since his unsuccessful pursuit of Daphne. In the Bible, the sweet-bay is often an emblem of prosperity and fame. In Christianity it is said to symbolize the Resurrection of Christ and the triumph of Humanity thereby. It is also the source of the word baccalaureate (laurel berry), and of poet laureate. Some evidence from the medical literature supports Bay Laurel having these uses: - Antioxidative: Fitoterapia. 2003 Sep;74(6):613-6. - Analgesic and anti-inflammatory: Phytother Res. 2003 Aug;17(7):733-6. - Anticonvulsant (antiepileptic): Phytomedicine. 2002 Apr;9(3):212-6. In Chinese folklore there is a great laurel tree on the moon, and the Chinese name for the laurel, 月桂, literally translates to "moon-laurel". This is the subject of a story of Wu Gang, a man who aspired to immortality and neglected his work. When the deities discovered this they sentenced Wu Gang to fell the laurel tree, whereupon he could join the ranks of the deities; however, since the laurel regenerated immediately when cut, it could never be felled. The phrase 吴刚伐木 ("Wu Gang felling the tree") is sometimes used to refer to endless toil, analogous to Sisyphus in Greek mythology. It is also widely cultivated as an ornamental plant in regions with mediterranean or oceanic climates, and as an indoor plant in colder regions. Bay leaves are eaten by the caterpillars of some Lepidoptera, for example the Eastern tiger swallowtail (Papilio glaucus). - Bay Laurel grown in a kitchen for bay leaves Bay Laurel grown in a kitchen for bay leaves - 19th century illustration 19th century illustration # Trivia Template:Trivia - Bay laurel leaves are used in the design of the 10 yen coin in Japan. - In Greek mythology, the tree was first formed when the nymph Daphne changed into it to escape the lustful pursuit of the Olympian god Apollo; see Apollo and Daphne. Daphne is the Greek name for the tree. - The National Emblem of Greece consists of a blue escutcheon with a white cross totally surrounded by two laurel branches. # External links - MeSH: Laurus - Laurus nobilis (Bay Laurel) - MeSH: Umbellularia - Umbellularia californica (California Bay Laurel) - MeSH: 3-oxo-eudesma-1,4(15),11(13)triene-12,6alpha-olide [Substance Name] - MeSH: anhydroperoxycostunolide [Substance Name] - MeSH: magnolialide [Substance Name] - PubMed search: "Laurus"[MAJR] - PubMed search: "anhydroperoxycostunolide" OR "magnolialide" OR "3-oxo-eudesma-1,4(15),11(13)triene-12,6alpha-olide" ca:Llorer cs:Vavřín ušlechtilý da:Ægte Laurbær de:Echter Lorbeer eo:Laŭro it:Laurus nobilis he:ער אציל hu:Babér nl:Laurier nrm:Louothi sr:Ловор fi:Laakeripuu sv:Lager (växt) Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Bay_Laurel
e99752efa937b8ed58aa7ad2991b96f365c91df1	wikidoc	Heart rate	Heart rate # Overview Heart rate is a term used to describe the frequency of the cardiac cycle. It is considered one of the four vital signs. Usually it is calculated as the number of contractions (heart beats) of the heart in one minute and expressed as "beats per minute" (bpm). See "Heart" for information on embryofetal heart rates. When resting, the average adult human heart beats at about 70 bpm (males) and 75 bpm (females); however, this rate varies among people and can be significantly lower in athletes. The infant/neonatal rate of heartbeat is around 130-150 bpm, the toddler's about 100–130 bpm, the older child's about 90–110 bpm, and the adolescent's about 80–100 bpm. The pulse is the most commonly used method of measuring the heart rate. This method may be inaccurate in cases of low cardiac output, as happens in some arrhythmias, where the heart rate may be considerably higher than the pulse rate. Listening to heart sounds using a stethescope, a process known as Auscultation, is a more accurate method of measuring the heart rate. # Measuring heart rate The pulse rate (which in most people is identical to the heart rate) can be measured at any point on the body where an artery's pulsation is transmitted to the surface - often as it is compressed against an underlying structure like bone. Some commonly palpated sites are as listed. - The inside of the wrist on the side of the thumb (radial artery) , (and less commonly ulnar artery on the pinky side which is deeper and harder to palpate ) - The neck (carotid artery), - The inside of the elbow, or under the biceps muscle (brachial artery) - The groin (femoral artery), - Behind the medial malleolus on the feet (posterior tibial artery) - Middle of dorsum of the foot (dorsalis pedis). - Behind the knee (popliteal artery) - Over the abdomen (abdominal aorta) - The chest. (aorta)This can be felt with one's hands or fingers but it is possible to auscultate the heart by utilizing a stethoscope. NOTE: The thumb should never be used for measuring heart rate, as its strong pulse may interfere with discriminating the site of pulsation, and you may count the thumb's pulse accidentally when measuring' Producing an electrocardiogram, or ECG (also abbreviated EKG), is one of the most precise methods of heart rate measurement. Continuous electrocardiographic monitoring of the heart is routinely done in many clinical settings, especially in critical care medicine. Commercial heart rate monitors are also available, consisting of a chest strap with electrodes. The signal is transmitted to a wrist receiver for display. Heart rate monitors allow accurate measurements to be taken continuously and can be used during exercise when manual measurement would be difficult or impossible (such as when the hands are being used). ## The square counting method The square counting method is ideal for regular heart rates. Use the sequence 300-150-100-75-60-50-43-37. Count from the first QRS complex, the first thick line is 300, the next thick line 150 etc. Stop the sequence at the next QRS complex. When the second QRS complex is between two lines, take the mean of the two numbers from the sequence. ## The marker method Non-regular rhythms are best determined with the "3 second marker method". Count the number of QRS complexes that fit into 3 seconds (some ECG writers print this period on the ECG paper). Multiply this number by 20 to find the number of beats/minute. # Maximum heart rate Maximum heart rate (also called MHR, or HRmax) is the highest number of times your heart can contract in one minute, or the heart rate that a person could achieve during maximal physical exertion. It is not the maximum one should obtain often during exercise. MHR is used as a base number to calculate target heart rate for exercise (see below). Research indicates it is most closely linked to a person's age; a person's HRmax will decline as they age. People who have participated in sports and athletic activities in early years will have a higher MHR than those less active as children. ## Measuring HRmax The most accurate way of measuring HRmax for an individual is via a cardiac stress test. In such a test, the subject exercises while being monitored by an electrocardiogram (ECG). During the test, the intensity of exercise is periodically increased (if a treadmill is being used, through increase in speed or slope of the treadmill) until the subject can no longer continue, or until certain changes in heart function are detected in the ECG (at which point the subject is directed to stop). Typical durations of such a test range from 10 to 20 minutes. Since the HRmax declines with age, this test does not hold permanent value. A less costly way to calculate is to warm up thoroughly on a bike (maybe 15 minutes on the flats). On a long, steady hill (doesn't have to be steep) increase effort every minute for at least 5 minutes until you can't go any faster (sitting, not standing). Then full-out sprint for 15 seconds (it is OK to stand at this point). Stop, get off the bike (this is for safety reasons - not mandatory) and immediately check your heart rate at its maximum for a full 60 seconds this is because 30 seconds and doubling it is inaccurate as you may have a heart Problem and it may change in the last sector of the reading. Many exercise machines (stationary bikes, treadmills, etc) have a built-in heart rate monitors. To ensure you are getting an accurate MHR reading, it's best to do this test on different days. Also, if you are doing this at a health club, try using various machines. Conducting a maximal exercise test can require expensive equipment. If you are just beginning an exercise regimen, you should only perform this test in the presence of medical staff due to risks associated with high heart rates. Instead, people typically use a formula to estimate their individual Maximum Heart Rate. The most common formula encountered is: This is attributed to various sources, often "Fox and Haskell". While the most common (and easy to remember and calculate), this particular formula is not considered by some to be a good predictor of HRmax. A 2003 study of 43 different formulae for HRmax (including the one above) concluded the following: 1) No "acceptable" formula currently existed, (they used the term "acceptable" to mean acceptable for both prediction of V_{\mathrm{O}_2 max}, and prescription of exercise training HR ranges) 2) The most accurate formula of those examined was: This was found to have a Standard Deviation that, although large (6.4 bpm), was still deemed to be acceptable for the use of prescribing exercise training HR ranges. Other often cited formulae are: (Often attributed to "Londeree and Moeschberger from the University of Missouri–Columbia") (Often attributed to "Miller et al. from Indiana University") These figures are still dependent on physiology and fitness - for example an endurance runner's rates will typically be lower due to the increased size of the heart required to support the exercise, while a sprinter's rates will be higher due to the improved response time and short duration. Also, averages are just that. You can have two 40 year old males with same height, weight, strength, etc. 220-40=180. But these two males could have a MHR 20 beats apart (e.g. 170-190). It's important to not guess. # Recovery heart rate This is the heart rate that our body will decrease to after an exercise session. For example, you exercise for a 1/2 hour at 160 BPM. Two minutes after you stop exercising, your heart rate decreases to 95. The 95 would be your recovery heart rate. This is used to evaluate your fitness level after exercise. It is good to set a two minute time frame and see how many beats you recover in that time frame. Compare this recover heart rate between exercise sessions. Measured over a 15-second sampling interval. NOTE: The thumb should never be used for measuring someone else's heart rate, as it has a pulse of its own. A drop of 20 beats in a minute is typical for a healthy person. A drop of less than 12 beats per minute after maximal exercise has been correlated with a significant increase in mortality . # Target heart rate Target heart rate (THR), or training heart rate, is a desired range of heart rate reached during aerobic exercise which enables one's heart and lungs to receive the most benefit from a workout. This theoretical range varies based on one's physical condition, age, and previous training. Below are two ways to calculate one's Target Heart Rate. In each of these methods, there is an element called "intensity" which is expressed as a percentage. THR can be calculated by using a range of 50%–85% intensity. However, it is crucial one have an accurate MHR calculation first to ensure these calculations are meaningful (see above). ## Effecting Heart Rate Having an increase in heart rate can be for a range of reasons; arousal, stress and anxiety; highly aroused individuals are mentally and physically activated; they experience increased heart rate, respiration and sweating. ## Karvonen method The Karvonen method factors in Resting Heart Rate (HRrest) to calculate Target Heart Rate (THR): Example for someone with a HRmax of 180 and a HRrest of 70: 50% intensity: ((180 − 70) × 0.50) + 70 = 125 bpm 85% intensity: ((180 − 70) × 0.85) + 70 = 163 bpm ## Zoladz method An alternative to the Karvonen method is the Zoladz method, which derives exercise zones by subtracting values from HRmax. Example for someone with a HRmax of 180: Zone 1 (easy exercise) : 180 - 50 = 130; ± 5 → 125 to 135 bpm Zone 4 (tough exercise): 180 - 20 = 160; ± 5 → 155 to 165 bpm # Heart rate reserve Heart rate reserve (HRR) is a term used to describe the difference between a person's measured or predicted maximum heart rate and resting heart rate. Some methods of measurement of exercise intensity measure percentage of heart rate reserve. Additionally, as a person increases their cardiovascular fitness, their HRrest will drop, thus the heart rate reserve will increase. Percentage of HRR is equivalent to percentage of VO2 reserve. # Heart rate abnormalities ## Tachycardia Tachycardia is a resting heart rate more than 100 beats per minute. This number can vary as smaller people and children have faster heart rates than adults. ## Bradycardia Bradycardia is defined as a heart rate less than 60 beats per minute although it is seldom symptomatic until below 50 bpm. Trained athletes tend to have slow resting heart rates, and resting bradycardia in athletes should not be considered abnormal if the individual has no symptoms associated with it. Again, this number can vary as smaller people and children have faster heart rates than adults. Miguel Indurain, a cyclist and five times Tour de France winner, had a resting heart rate of 28 beats per minute, one of the lowest ever recorded in a healthy human. # Related Chapters - Cardiology - Cardiac pacemaker - Pulse - Blood flow - Blood pressure - Athlete's heart - Procoralan - Heart # Sources - Copyleft images obtained courtesy of ECGpedia, :NewFiles&dir=prev&offset=20080806182927&limit=500	Heart rate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Heart rate is a term used to describe the frequency of the cardiac cycle. It is considered one of the four vital signs. Usually it is calculated as the number of contractions (heart beats) of the heart in one minute and expressed as "beats per minute" (bpm). See "Heart" for information on embryofetal heart rates. When resting, the average adult human heart beats at about 70 bpm (males) and 75 bpm (females); however, this rate varies among people and can be significantly lower in athletes. The infant/neonatal rate of heartbeat is around 130-150 bpm, the toddler's about 100–130 bpm, the older child's about 90–110 bpm, and the adolescent's about 80–100 bpm. The pulse is the most commonly used method of measuring the heart rate. This method may be inaccurate in cases of low cardiac output, as happens in some arrhythmias, where the heart rate may be considerably higher than the pulse rate. Listening to heart sounds using a stethescope, a process known as Auscultation, is a more accurate method of measuring the heart rate. # Measuring heart rate The pulse rate (which in most people is identical to the heart rate) can be measured at any point on the body where an artery's pulsation is transmitted to the surface - often as it is compressed against an underlying structure like bone. Some commonly palpated sites are as listed. - The inside of the wrist on the side of the thumb (radial artery) , (and less commonly ulnar artery on the pinky side which is deeper and harder to palpate ) - The neck (carotid artery), - The inside of the elbow, or under the biceps muscle (brachial artery) - The groin (femoral artery), - Behind the medial malleolus on the feet (posterior tibial artery) - Middle of dorsum of the foot (dorsalis pedis). - Behind the knee (popliteal artery) - Over the abdomen (abdominal aorta) - The chest. (aorta)This can be felt with one's hands or fingers but it is possible to auscultate the heart by utilizing a stethoscope. NOTE: The thumb should never be used for measuring heart rate, as its strong pulse may interfere with discriminating the site of pulsation, and you may count the thumb's pulse accidentally when measuring'[1] Producing an electrocardiogram, or ECG (also abbreviated EKG), is one of the most precise methods of heart rate measurement. Continuous electrocardiographic monitoring of the heart is routinely done in many clinical settings, especially in critical care medicine. Commercial heart rate monitors are also available, consisting of a chest strap with electrodes. The signal is transmitted to a wrist receiver for display. Heart rate monitors allow accurate measurements to be taken continuously and can be used during exercise when manual measurement would be difficult or impossible (such as when the hands are being used). ## The square counting method The square counting method is ideal for regular heart rates. Use the sequence 300-150-100-75-60-50-43-37. Count from the first QRS complex, the first thick line is 300, the next thick line 150 etc. Stop the sequence at the next QRS complex. When the second QRS complex is between two lines, take the mean of the two numbers from the sequence. ## The marker method Non-regular rhythms are best determined with the "3 second marker method". Count the number of QRS complexes that fit into 3 seconds (some ECG writers print this period on the ECG paper). Multiply this number by 20 to find the number of beats/minute. # Maximum heart rate Maximum heart rate (also called MHR, or HRmax) is the highest number of times your heart can contract in one minute, or the heart rate that a person could achieve during maximal physical exertion. It is not the maximum one should obtain often during exercise. MHR is used as a base number to calculate target heart rate for exercise (see below). Research indicates it is most closely linked to a person's age; a person's HRmax will decline as they age. [2] People who have participated in sports and athletic activities in early years will have a higher MHR than those less active as children. ## Measuring HRmax The most accurate way of measuring HRmax for an individual is via a cardiac stress test. In such a test, the subject exercises while being monitored by an electrocardiogram (ECG). During the test, the intensity of exercise is periodically increased (if a treadmill is being used, through increase in speed or slope of the treadmill) until the subject can no longer continue, or until certain changes in heart function are detected in the ECG (at which point the subject is directed to stop). Typical durations of such a test range from 10 to 20 minutes. Since the HRmax declines with age, this test does not hold permanent value. A less costly way to calculate is to warm up thoroughly on a bike (maybe 15 minutes on the flats). On a long, steady hill (doesn't have to be steep) increase effort every minute for at least 5 minutes until you can't go any faster (sitting, not standing). Then full-out sprint for 15 seconds (it is OK to stand at this point). Stop, get off the bike (this is for safety reasons - not mandatory) and immediately check your heart rate at its maximum for a full 60 seconds this is because 30 seconds and doubling it is inaccurate as you may have a heart Problem and it may change in the last sector of the reading. Many exercise machines (stationary bikes, treadmills, etc) have a built-in heart rate monitors. To ensure you are getting an accurate MHR reading, it's best to do this test on different days. Also, if you are doing this at a health club, try using various machines. Conducting a maximal exercise test can require expensive equipment. If you are just beginning an exercise regimen, you should only perform this test in the presence of medical staff due to risks associated with high heart rates. Instead, people typically use a formula to estimate their individual Maximum Heart Rate. The most common formula encountered is: This is attributed to various sources, often "Fox and Haskell". While the most common (and easy to remember and calculate), this particular formula is not considered by some to be a good predictor of HRmax. A 2003 study [2] of 43 different formulae for HRmax (including the one above) concluded the following: 1) No "acceptable" formula currently existed, (they used the term "acceptable" to mean acceptable for both prediction of <math>V_{\mathrm{O}_2 max}</math>, and prescription of exercise training HR ranges) 2) The most accurate formula of those examined was: This was found to have a Standard Deviation that, although large (6.4 bpm), was still deemed to be acceptable for the use of prescribing exercise training HR ranges. Other often cited formulae are: (Often attributed to "Londeree and Moeschberger from the University of Missouri–Columbia") (Often attributed to "Miller et al. from Indiana University") These figures are still dependent on physiology and fitness - for example an endurance runner's rates will typically be lower due to the increased size of the heart required to support the exercise, while a sprinter's rates will be higher due to the improved response time and short duration. Also, averages are just that. You can have two 40 year old males with same height, weight, strength, etc. 220-40=180. But these two males could have a MHR 20 beats apart (e.g. 170-190). It's important to not guess. # Recovery heart rate This is the heart rate that our body will decrease to after an exercise session. For example, you exercise for a 1/2 hour at 160 BPM. Two minutes after you stop exercising, your heart rate decreases to 95. The 95 would be your recovery heart rate. This is used to evaluate your fitness level after exercise. It is good to set a two minute time frame and see how many beats you recover in that time frame. Compare this recover heart rate between exercise sessions. Measured over a 15-second sampling interval. NOTE: The thumb should never be used for measuring someone else's heart rate, as it has a pulse of its own.[2] A drop of 20 beats in a minute is typical for a healthy person. A drop of less than 12 beats per minute after maximal exercise has been correlated with a significant increase in mortality [3]. # Target heart rate Target heart rate (THR), or training heart rate, is a desired range of heart rate reached during aerobic exercise which enables one's heart and lungs to receive the most benefit from a workout. This theoretical range varies based on one's physical condition, age, and previous training. Below are two ways to calculate one's Target Heart Rate. In each of these methods, there is an element called "intensity" which is expressed as a percentage. THR can be calculated by using a range of 50%–85% intensity. However, it is crucial one have an accurate MHR calculation first to ensure these calculations are meaningful (see above). ## Effecting Heart Rate Having an increase in heart rate can be for a range of reasons; arousal, stress and anxiety; highly aroused individuals are mentally and physically activated; they experience increased heart rate, respiration and sweating. ## Karvonen method The Karvonen method factors in Resting Heart Rate (HRrest) to calculate Target Heart Rate (THR): Example for someone with a HRmax of 180 and a HRrest of 70: 50% intensity: ((180 − 70) × 0.50) + 70 = 125 bpm 85% intensity: ((180 − 70) × 0.85) + 70 = 163 bpm ## Zoladz method An alternative to the Karvonen method is the Zoladz method, which derives exercise zones by subtracting values from HRmax. Example for someone with a HRmax of 180: Zone 1 (easy exercise) : 180 - 50 = 130; ± 5 → 125 to 135 bpm Zone 4 (tough exercise): 180 - 20 = 160; ± 5 → 155 to 165 bpm # Heart rate reserve Heart rate reserve (HRR) is a term used to describe the difference between a person's measured or predicted maximum heart rate and resting heart rate. Some methods of measurement of exercise intensity measure percentage of heart rate reserve. Additionally, as a person increases their cardiovascular fitness, their HRrest will drop, thus the heart rate reserve will increase. Percentage of HRR is equivalent to percentage of VO2 reserve. # Heart rate abnormalities ## Tachycardia Tachycardia is a resting heart rate more than 100 beats per minute. This number can vary as smaller people and children have faster heart rates than adults. ## Bradycardia Bradycardia is defined as a heart rate less than 60 beats per minute although it is seldom symptomatic until below 50 bpm. Trained athletes tend to have slow resting heart rates, and resting bradycardia in athletes should not be considered abnormal if the individual has no symptoms associated with it. Again, this number can vary as smaller people and children have faster heart rates than adults. Miguel Indurain, a cyclist and five times Tour de France winner, had a resting heart rate of 28 beats per minute, one of the lowest ever recorded in a healthy human.[3] # Related Chapters - Cardiology - Cardiac pacemaker - Pulse - Blood flow - Blood pressure - Athlete's heart - Procoralan - Heart # Sources - Copyleft images obtained courtesy of ECGpedia, http://en.ecgpedia.org/index.php?title=Special:NewFiles&dir=prev&offset=20080806182927&limit=500	https://www.wikidoc.org/index.php/Beats_per_minute
55c41f956d4112fbdc2fe365d9956529b619d6c7	wikidoc	Belatacept	Belatacept # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Belatacept is an immunological agent that is FDA approved for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Adult Kidney Transplant Recipients - Belatacept is indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant. NULOJIX is to be used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids. Limitations of Use - Use belatacept only in patients who are EBV seropositive. - Use of belatacept for the prophylaxis of organ rejection in transplanted organs other than kidney has not been established. # Dosage Dosage in Adult Kidney Transplant Recipients - Belatacept should be administered in combination with basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids. In clinical trials the median (25th-75th percentile) corticosteroid doses were tapered to approximately 15 mg (10-20 mg) per day by the first 6 weeks and remained at approximately 10 mg (5-10 mg) per day for the first 6 months post-transplant. Corticosteroid utilization should be consistent with the belatacept clinical trial experience. - Due to an increased risk of post-transplant lymphoproliferative disorder (PTLD) predominantly involving the central nervous system (CNS), progressive multifocal leukoencephalopathy (PML), and serious CNS infections, administration of higher than the recommended doses or more frequent dosing of belatacept is not recommended. - Belatacept is for intravenous infusion only. Patients do not require premedication prior to administration of belatacept. - Dosing instructions are provided in Table 1. - The total infusion dose of belatacept should be based on the actual body weight of the patient at the time of transplantation, and should not be modified during the course of therapy, unless there is a change in body weight of greater than 10%. - The prescribed dose of belatacept must be evenly divisible by 12.5 mg in order for the dose to be prepared accurately using the reconstituted solution and the silicone-free disposable syringe provided. Evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100. For example: - A patient weighs 64 kg. The dose is 10 mg per kg. - Calculated Dose: 64 kg × 10 mg per kg = 640 mg - The closest doses evenly divisible by 12.5 mg below and above 640 mg are 637.5 mg and 650 mg. - The nearest dose to 640 mg is 637.5 mg. - Therefore, the actual prescribed dose for the patient should be 637.5 mg. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belatacept in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belatacept in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Belatacept in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belatacept in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belatacept in pediatric patients. # Contraindications There is limited information regarding Belatacept Contraindications in the drug label. # Warnings ## Post-Transplant Lymphoproliferative Disorder - Belatacept-treated patients have an increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared to patients on a cyclosporine-based regimen. As the total burden of immunosuppression is a risk factor for PTLD, higher than the recommended doses or more frequent dosing of belatacept and higher than recommended doses of concomitant immunosuppressive agents are not recommended. Physicians should consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms. EBV Serostatus - The risk of PTLD was higher in EBV seronegative patients compared to EBV seropositive patients. EBV seropositive patients are defined as having evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA). - Epstein-Barr virus serology should be ascertained before starting administration of belatacept, and only patients who are EBV seropositive should receive belatacept. Transplant recipients who are EBV seronegative, or with unknown serostatus, should not receive belatacept. Other Risk Factors - Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell-depleting therapy. T-cell-depleting therapies to treat acute rejection should be used cautiously. CMV prophylaxis is recommended for at least 3 months after transplantation. - Patients who are EBV seropositive and CMV seronegative may be at increased risk for PTLD compared to patients who are EBV seropositive and CMV seropositive. Since CMV seronegative patients are at increased risk for CMV disease (a known risk factor for PTLD), the clinical significance of CMV serology for PTLD remains to be determined; however, these findings should be considered when prescribing belatacept. ## Management of Immunosuppression - Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe belatacept. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient. ## Other Malignancies - Patients receiving immunosuppressants, including belatacept, are at increased risk of developing malignancies, in addition to PTLD, including the skin. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. ## Progressive Multifocal Leukoencephalopathy - Progressive multifocal leukoencephalopathy (PML) is an often rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC virus, a human polyoma virus. In clinical trials with belatacept, two cases of PML were reported in patients receiving belatacept at higher cumulative doses and more frequently than the recommended regimen, along with mycophenolate mofetil (MMF) and corticosteroids; one case occurred in a kidney transplant recipient and the second case occurred in a liver transplant recipient. As PML has been associated with high levels of overall immunosuppression, the recommended doses and frequency of belatacept and concomitant immunosuppressives, including MMF, should not be exceeded. - Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. PML is usually diagnosed by brain imaging, cerebrospinal fluid (CSF) testing for JC viral DNA by polymerase chain reaction (PCR), and/or brain biopsy. Consultation with a specialist (e.g., neurologist and/or infectious disease) should be considered for any suspected or confirmed cases of PML. - If PML is diagnosed, consideration should be given to reduction or withdrawal of immunosuppression taking into account the risk to the allograft. ## Other Serious Infections - Patients receiving immunosuppressants, including belatacept, are at increased risk of developing bacterial, viral (cytomegalovirus and herpes), fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. - Prophylaxis for cytomegalovirus is recommended for at least 3 months after transplantation. Prophylaxis for Pneumocystis jiroveci is recommended after transplantation. Tuberculosis - Tuberculosis was more frequently observed in patients receiving belatacept than cyclosporine in clinical trials. Patients should be evaluated for tuberculosis and tested for latent infection prior to initiating belatacept. Treatment of latent tuberculosis infection should be initiated prior to belatacept use. Polyoma Virus Nephropathy - In addition to cases of JC virus-associated PML ,cases of polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, have been reported. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss . Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft. ## Liver Transplant - Use of belatacept in liver transplant patients is not recommended. In a clinical trial of liver transplant patients, use of belatacept regimens with more frequent administration of belatacept than any of those studied in kidney transplant, along with mycophenolate mofetil (MMF) and corticosteroids, was associated with a higher rate of graft loss and death compared to the tacrolimus control arms. In addition, two cases of PTLD involving the liver allograft (one fatal) and one fatal case of PML were observed among the 147 patients randomized to belatacept. The two cases of PTLD were reported among the 140 EBV seropositive patients (1.4%). The fatal case of PML was reported in a patient receiving higher than recommended doses of belatacept and MMF. ## Acute Rejection and Graft Loss with Corticosteroid Minimization - In postmarketing experience, use of belatacept in conjunction with basiliximab induction, MMF, and corticosteroid minimization to 5 mg per day between Day 3 and Week 6 post-transplant was associated with an increased rate and grade of acute rejection, particularly Grade III rejection. These Grade III rejections occurred in patients with 4 to 6 HLA mismatches. Graft loss was a consequence of Grade III rejection in some patients. - Corticosteroid utilization should be consistent with the belatacept clinical trial experience. ## Immunizations - The use of live vaccines should be avoided during treatment with belatacept, including but not limited to the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. # Adverse Reactions ## Clinical Trials Experience - The most serious adverse reactions reported with belatacept are: - PTLD, predominantly CNS PTLD, and other malignancies. - Serious infections, including JC virus-associated PML and polyoma virus nephropathy. Clinical Studies Experience - The data described below primarily derive from two randomized, active-controlled three-year trials of belatacept in de novo kidney transplant patients. In Study 1 and Study 2, belatacept was studied at the recommended dose and frequency in a total of 401 patients compared to a cyclosporine control regimen in a total of 405 patients. These two trials also included a total of 403 patients treated with a belatacept regimen of higher cumulative dose and more frequent dosing than recommended. All patients also received basiliximab induction, mycophenolate mofetil, and corticosteroids. Patients were treated and followed for 3 years. - CNS PTLD, PML, and other CNS infections were more frequently observed in association with a belatacept regimen of higher cumulative dose and more frequent dosing compared to the recommended regimen; therefore, administration of higher than the recommended doses and/or more frequent dosing of belatacept is not recommended. - The average age of patients in Studies 1 and 2 in the belatacept recommended dose and cyclosporine control regimens was 49 years, ranging from 18 to 79 years. Approximately 70% of patients were male; 67% were white, 11% were black, and 22% other races. About 25% of patients were from the United States and 75% from other countries. - Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. - The most commonly reported adverse reactions occurring in ≥20% of patients treated with the recommended dose and frequency of belatacept were anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia. - The proportion of patients who discontinued treatment due to adverse reactions was 13% for the recommended belatacept regimen and 19% for the cyclosporine control arm through three years of treatment. The most common adverse reactions leading to discontinuation in belatacept-treated patients were cytomegalovirus infection (1.5%) and complications of transplanted kidney (1.5%). - Information on selected significant adverse reactions observed during clinical trials is summarized below. Post-Transplant Lymphoproliferative Disorder - Reported cases of post-transplant lymphoproliferative disorder (PTLD) up to 36 months post transplant were obtained for belatacept by pooling both dosage regimens of belatacept in Studies 1 and 2 (804 patients) with data from a third study in kidney transplantation (Study 3, 145 patients) which evaluated two belatacept dosage regimens similar, but slightly different, from those of Studies 1 and 2 (see Table 2). The total number of belatacept patients from these three studies (949) was compared to the pooled cyclosporine control groups from all three studies (476 patients). - Among 401 patients in Studies 1 and 2 treated with the recommended regimen of belatacept and the 71 patients in Study 3 treated with a very similar (but non-identical) belatacept regimen, there were 5 cases of PTLD: 3 in EBV seropositive patients and 2 in EBV seronegative patients. Two of the 5 cases presented with CNS involvement. - Among the 477 patients in Studies 1, 2, and 3 treated with the belatacept regimen of higher cumulative dose and more frequent dosing than recommended, there were 8 cases of PTLD: 2 in EBV seropositive patients and 6 in EBV seronegative or serostatus unknown patients. Six of the 8 cases presented with CNS involvement. Therefore, administration of higher than the recommended doses or more frequent dosing of belatacept is not recommended. - One of the 476 patients treated with cyclosporine developed PTLD, without CNS involvement. - All cases of PTLD reported up to 36 months post transplant in belatacept- or cyclosporine-treated patients presented within 18 months of transplantation. - Overall, the rate of PTLD in 949 patients treated with any of the belatacept regimens was 9-fold higher in those who were EBV seronegative or EBV serostatus unknown (8/139) compared to those who were EBV seropositive (5/810 patients). Therefore belatacept is recommended for use only in patients who are EBV seropositive. EBV Seropositive Subpopulation - Among the 806 EBV seropositive patients with known CMV serostatus treated with either belatacept regimen in Studies 1, 2, and 3, two percent (2%; 4/210) of CMV seronegative patients developed PTLD compared to 0.2% (1/596) of CMV seropositive patients. Among the 404 EBV seropositive recipients treated with the recommended dosage regimen of belatacept, three PTLD cases were detected among 99 CMV seronegative patients (3%) and there was no case detected among 303 CMV seropositive patients. The clinical significance of CMV serology as a risk factor for PTLD remains to be determined; however, these findings should be considered when prescribing belatacept. Other Malignancies - Malignancies, excluding non-melanoma skin cancer and PTLD, were reported in Study 1 and Study 2 in 3.5% (14/401) of patients treated with the recommended belatacept regimen and 3.7% (15/405) of patients treated with the cyclosporine control regimen. Non-melanoma skin cancer was reported in 1.5% (6/401) of patients treated with the recommended belatacept regimen and in 3.7% (15/405) of patients treated with cyclosporine. Progressive Multifocal Leukoencephalopathy - Two fatal cases of progressive multifocal leukoencephalopathy (PML) have been reported among 1096 patients treated with a belatacept-containing regimen: one patient in clinical trials of kidney transplant (Studies 1, 2, and 3 described above) and one patient in a trial of liver transplant (trial of 250 patients). No cases of PML were reported in patients treated with the recommended belatacept regimen or the control regimen in these trials. - The kidney transplant recipient was treated with the belatacept regimen of higher cumulative dose and more frequent dosing than recommended, mycophenolate mofetil (MMF), and corticosteroids for 2 years. The liver transplant recipient was treated with 6 months of a belatacept dosage regimen that was more intensive than that studied in kidney transplant recipients, MMF at doses higher than the recommended dose, and corticosteroids. Bacterial, Mycobacterial, Viral, and Fungal Infections - Adverse reactions of infectious etiology were reported based on clinical assessment by physicians. The causative organisms for these reactions are identified when provided by the physician. The overall number of infections, serious infections, and select infections with identified etiology reported in patients treated with the belatacept recommended regimen or the cyclosporine control in Studies 1 and 2 are shown in Table 3. Fungal infections were reported in 18% of patients receiving belatacept compared to 22% receiving cyclosporine, primarily due to skin and mucocutaneous fungal infections. Tuberculosis and herpes infections were reported more frequently in patients receiving belatacept than cyclosporine. Of the patients who developed tuberculosis through 3 years, all but one belatacept patient lived in countries with a high prevalence of tuberculosis. Infections Reported in the CNS - Following three years of treatment in Studies 1 and 2, cryptococcal meningitis was reported in one patient out of 401 patients treated with the belatacept recommended regimen (0.2%) and one patient out of the 405 treated with the cyclosporine control (0.2%). - Six patients out of the 403 who were treated with the belatacept regimen of higher cumulative dose and more frequent dosing than recommended in Studies 1 and 2 (1.5%) were reported to have developed CNS infections, including 2 cases of cryptococcal meningitis, one case of Chagas encephalitis with cryptococcal meningitis, one case of cerebral aspergillosis, one case of West Nile encephalitis, and one case of PML (discussed above). Infusion Reactions - There were no reports of anaphylaxis or drug hypersensitivity in patients treated with belatacept in Studies 1 and 2 through three years. - Infusion-related reactions within one hour of infusion were reported in 5% of patients treated with the recommended dose of belatacept, similar to the placebo rate. No serious events were reported through Year 3. The most frequent reactions were hypotension and hypertension. Proteinuria - At Month 1 after transplantation in Studies 1 and 2, the frequency of 2+ proteinuria on urine dipstick in patients treated with the belatacept recommended regimen was 33% (130/390) and 28% (107/384) in patients treated with the cyclosporine control regimen. The frequency of 2+ proteinuria was similar between the two treatment groups between one and three years after transplantation (<10% in both studies). There were no differences in the occurrence of 3+ proteinuria (<4% in both studies) at any time point, and no patients experienced 4+ proteinuria. The clinical significance of this increase in early proteinuria is unknown. Immunogenicity - Antibodies directed against the belatacept molecule were assessed in 398 patients treated with the belatacept recommended regimen in Studies 1 and 2 (212 of these patients were treated for at least 2 years). Of the 372 patients with immunogenicity assessment at baseline (prior to receiving belatacept treatment), 29 patients tested positive for anti-belatacept antibodies; 13 of these patients had antibodies to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Anti-belatacept antibody titers did not increase during treatment in these 29 patients. - Eight (2%) patients developed antibodies during treatment with the belatacept recommended regimen. In the patients who developed antibodies during treatment, the median titer (by dilution method) was 8, with a range of 5 to 80. Of 56 patients who tested negative for antibodies during treatment and reassessed approximately 7 half-lives after discontinuation of belatacept, 1 tested antibody positive. Anti-belatacept antibody development was not associated with altered clearance of belatacept. - Samples from 6 patients with confirmed binding activity to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) region of the belatacept molecule were assessed by an in vitro bioassay for the presence of neutralizing antibodies. Three of these 6 patients tested positive for neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. - The clinical impact of anti-belatacept antibodies (including neutralizing anti-belatacept antibodies) could not be determined in the studies. - The data reflect the percentage of patients whose test results were positive for antibodies to belatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belatacept with the incidence of antibodies to other products may be misleading. New-Onset Diabetes After Transplantation - The incidence of new-onset diabetes after transplantation (NODAT) was defined in Studies 1 and 2 as use of an antidiabetic agent for ≥30 days or ≥2 fasting plasma glucose values ≥126 mg/dL (7.0 mmol/L) post-transplantation. Of the patients treated with the belatacept recommended regimen, 5% (14/304) developed NODAT by the end of one year compared to 10% (27/280) of patients on the cyclosporine control regimen. However, by the end of the third year, the cumulative incidence of NODAT was 8% (24/304) in patients treated with the belatacept recommended regimen and 10% (29/280) in patients treated with the cyclosporine regimen. Hypertension - Blood pressure and use of antihypertensive medications were reported in Studies 1 and 2. By Year 3, one or more antihypertensive medications were used in 85% of belatacept-treated patients and 92% of cyclosporine-treated patients. At one year after transplantation, systolic blood pressures were 8 mmHg lower and diastolic blood pressures were 3 mmHg lower in patients treated with the belatacept recommended regimen compared to the cyclosporine control regimen. At three years after transplantation, systolic blood pressures were 6 mmHg lower and diastolic blood pressures were 3 mmHg lower in belatacept-treated patients compared to cyclosporine-treated patients. Hypertension was reported as an adverse reaction in 32% of belatacept-treated patients and 37% of cyclosporine-treated patients (see Table 4). Dyslipidemia - Mean values of total cholesterol, HDL, LDL, and triglycerides were reported in Studies 1 and 2. At one year after transplantation these values were 183 mg/dL, 50 mg/dL, 102 mg/dL, and 151 mg/dL, respectively, in 401 patients treated with the belatacept recommended regimen and 196 mg/dL, 48 mg/dL, 108 mg/dL, and 195 mg/dL, respectively, in 405 patients treated with the cyclosporine control regimen. At three years after transplantation, the total cholesterol, HDL, LDL, and triglycerides were 176 mg/dL, 49 mg/dL, 100 mg/dL, and 141 mg/dL, respectively, in belatacept-treated patients compared to 193 mg/dL, 48 mg/dL, 106 mg/dL, and 180 mg/dL in cyclosporine-treated patients. - The clinical significance of the lower mean triglyceride values in belatacept-treated patients at one and three years is unknown. Other Adverse Reactions - Adverse reactions that occurred at a frequency of ≥10% in patients treated with the belatacept recommended regimen or cyclosporine control regimen in Studies 1 and 2 through three years are summarized by preferred term in decreasing order of frequency within Table 4. - Selected adverse reactions occurring in <10% from belatacept-treated patients in either regimen through three years in Studies 1 and 2 are listed below: - Immune System Disorders: Guillain-Barré syndrome - Infections and Infestations: see Table 3 - Gastrointestinal Disorders: stomatitis, including aphthous stomatitis - Injury, Poisoning, and Procedural Complications: chronic allograft nephropathy, complications of transplanted kidney, including wound dehiscence, arteriovenous fistula thrombosis - Blood and Lymphatic System Disorders: neutropenia - Renal and Urinary Disorders: renal impairment, including acute renal failure, renal artery stenosis, urinary incontinence, hydronephrosis - Vascular Disorders: hematoma, lymphocele - Musculoskeletal and Connective Tissue Disorders: musculoskeletal pain - Skin and Subcutaneous Tissue Disorders: alopecia, hyperhidrosis - Cardiac Disorders: atrial fibrillation ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Belatacept in the drug label. # Drug Interactions Mycophenolate Mofetil (MMF) - Monitor for a need to adjust concomitant mycophenolate mofetil (MMF) dosage when patient’s therapy is switched between cyclosporine and belatacept, as cyclosporine decreases mycophenolic acid (MPA) exposure by preventing enterohepatic recirculation of MPA while belatacept does not: - A higher MMF dosage may be needed after switching from belatacept to cyclosporine, since this may result in lower MPA concentrations and increase the risk of graft rejection. - A lower MMF dosage may be needed after switching from cyclosporine to belatacept, since this may result in higher MPA concentrations and increase the risk for adverse reactions related to MPA (review the Full Prescribing Information for MMF). Cytochrome P450 Substrates - No dosage adjustments are needed for drugs metabolized via CYP1A2, CYP2C9, CYP2D6, CYP3A, and CYP2C19 when coadministered with belatacept # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C - Belatacept should not be used in pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. There are no studies of belatacept treatment in pregnant women. Belatacept is known to cross the placenta of animals. Belatacept was not teratogenic in pregnant rats and rabbits at doses approximately 16 and 19 times greater than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg per kg administered over the first month of treatment, based on area under the concentration-time curve (AUC). - Belatacept administered to female rats daily during gestation and throughout the lactation period was associated with maternal toxicity (infections) in a small percentage of dams at doses of ≥20 mg per kg (≥3 times the MRHD exposure based on AUC) resulting in increased pup mortality (up to 100% pup mortality in some dams). In pups that survived, there were no abnormalities or malformations at doses up to 200 mg per kg (19 times the MRHD exposure). - In vitro data indicate that belatacept has lower binding affinity to CD80/CD86 and lower potency in rodents than in humans. Although the rat toxicity studies with belatacept were done at pharmacologically saturating doses, the in vivo difference in potency between rats and humans is unknown. Therefore, the relevance of the rat toxicities to humans and the significance of the magnitude of the relative exposures (rats: humans) are unknown. - Abatacept, a fusion protein that differs from belatacept by 2 amino acids, binds to the same ligands (CD80/CD86) and blocks T-cell costimulation like belatacept, but is more active than belatacept in rodents. Therefore, toxicities identified with abatacept in rodents, including infections and autoimmunity, may be predictive of adverse effects in humans treated with belatacept. - Autoimmunity was observed in one rat offspring exposed to abatacept in utero and/or during lactation and in juvenile rats after treatment with abatacept. However, the clinical relevance of autoimmunity in rats to patients or a fetus exposed in utero is unknown. - Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women who have received belatacept or whose partners have received belatacept, healthcare providers are strongly encouraged to register pregnant patients in the National Transplant Pregnancy Registry (NTPR) by calling 1-877-955-6877. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belatacept in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Belatacept during labor and delivery. ### Nursing Mothers - It is not known whether belatacept is excreted in human milk or absorbed systemically after ingestion by a nursing infant. However, belatacept is excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from belatacept in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and efficacy of belatacept in patients under 18 years of age have not been established. Because T cell development continues into the teenage years, the potential concern for autoimmunity in neonates applies to pediatric use as well. ### Geriatic Use - Of 401 patients treated with the recommended dosage regimen of belatacept, 15% were 65 years of age and older, while 3% were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity or less efficacy in older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Belatacept with respect to specific gender populations. ### Race There is no FDA guidance on the use of Belatacept with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Belatacept in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Belatacept in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Belatacept in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Belatacept in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous Preparation and Administration Instructions - Belatacept is for intravenous infusion only. - Caution: NULOJIX must be reconstituted/prepared using only the silicone-free disposable syringe provided with each vial. - If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Bristol-Myers Squibb at 1-888-NULOJIX. Preparation for Administration - Calculate the number of belatacept vials required to provide the total infusion dose. Each vial contains 250 mg of belatacept lyophilized powder. - Reconstitute the contents of each vial of belatacept with 10.5 mL of a suitable diluent using the silicone-free disposable syringe provided with each vial and an 18- to 21-gauge needle. Suitable diluents include: sterile water for injection (SWFI), 0.9% sodium chloride (NS), or 5% dextrose in water (D5W). Note: If the belatacept powder is accidentally reconstituted using a different syringe than the one provided, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes. - To reconstitute the belatacept powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of diluent (10.5 mL of SWFI, NS, or D5W) to the glass wall of the vial. - To minimize foam formation, rotate the vial and invert with gentle swirling until the contents are completely dissolved. Avoid prolonged or vigorous agitation. Do not shake. - The reconstituted solution contains a belatacept concentration of 25 mg/mL and should be clear to slightly opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present. - Calculate the total volume of the reconstituted 25 mg/mL belatacept solution required to provide the total infusion dose. Volume of 25 mg/mL belatacept solution (in mL) = Prescribed Dose (in mg) ÷ 25 mg/mL - Prior to intravenous infusion, the required volume of the reconstituted belatacept solution must be further diluted with a suitable infusion fluid (NS or D5W). belatacept reconstituted with: - SWFI should be further diluted with either NS or D5W - NS should be further diluted with NS - D5W should be further diluted with D5W - From the appropriate size infusion bag or bottle, withdraw a volume of infusion fluid that is equal to the volume of the reconstituted belatacept solution required to provide the prescribed dose. With the same silicone-free disposable syringe used for reconstitution, withdraw the required amount of belatacept solution from the vial, inject it into the infusion bag or bottle, and gently rotate the infusion bag or bottle to ensure mixing. The final belatacept concentration in the infusion bag or bottle should range from 2 mg/mL to 10 mg/mL. Typically, an infusion volume of 100 mL will be appropriate for most patients and doses, but total infusion volumes ranging from 50 mL to 250 mL may be used. Any unused solution remaining in the vials must be discarded. - Prior to administration, the belatacept infusion should be inspected visually for particulate matter and discoloration. Discard the infusion if any particulate matter or discoloration is observed. - The entire belatacept infusion should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 µm). - The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The belatacept infusion must be completed within 24 hours of reconstitution of the belatacept lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°-8°C (36°-46°F) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20°-25°C and room light). - Infuse belatacept in a separate line from other concomitantly infused agents. Belatacept should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of belatacept with other agents. ### Monitoring There is limited information regarding Monitoring of Belatacept in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Belatacept in the drug label. # Overdosage - Single doses up to 20 mg per kg of NULOJIX have been administered to healthy subjects without apparent toxic effect. The administration of NULOJIX of higher cumulative dose and more frequent dosing than recommended in kidney transplant patients resulted in a higher frequency of CNS-related adverse reactions. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted # Pharmacology ## Mechanism of Action - Belatacept, a selective T-cell (lymphocyte) costimulation blocker, binds to CD80 and CD86 on antigen-presenting cells thereby blocking CD28 mediated costimulation of T lymphocytes. In vitro, belatacept inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-γ, interleukin-4, and TNF-α. Activated T lymphocytes are the predominant mediators of immunologic rejection. - In non-human primate models of renal transplantation, belatacept monotherapy prolonged graft survival and decreased the production of anti-donor antibodies, compared to vehicle. ## Structure - NULOJIX® (belatacept), a selective T-cell costimulation blocker, is a soluble fusion protein consisting of the modified extracellular domain of CTLA-4 fused to a portion (hinge-CH2-CH3 domains) of the Fc domain of a human immunoglobulin G1 antibody. Belatacept is produced by recombinant DNA technology in a mammalian cell expression system. Two amino acid substitutions (L104 to E; A29 to Y) were made in the ligand binding region of CTLA-4. As a result of these modifications, belatacept binds CD80 and CD86 more avidly than abatacept, the parent CTLA4-Immunoglobulin (CTLA4-Ig) molecule from which it is derived. The molecular weight of belatacept is approximately 90 kilodaltons. - Belatacept is supplied as a sterile, white or off-white lyophilized powder for intravenous administration. Prior to use, the lyophile is reconstituted with a suitable fluid to obtain a clear to slightly opalescent, colorless to pale yellow solution, with a pH in the range of 7.2 to 7.8. Suitable fluids for constitution of the lyophile include SWFI, 0.9% NS, or D5W . Each 250 mg single-use vial of belatacept also contains: monobasic sodium phosphate (34.5 mg), sodium chloride (5.8 mg), and sucrose (500 mg). ## Pharmacodynamics - Belatacept-mediated costimulation blockade results in the inhibition of cytokine production by T cells required for antigen-specific antibody production by B cells. In clinical trials, greater reductions in mean immunoglobulin (IgG, IgM, and IgA) concentrations were observed from baseline to Month 6 and Month 12 post-transplant in belatacept-treated patients compared to cyclosporine-treated patients. In an exploratory subset analysis, a trend of decreasing IgG concentrations with increasing belatacept trough concentrations was observed at Month 6. Also in this exploratory subset analysis, belatacept-treated patients with CNS PTLD, CNS infections including PML, other serious infections, and malignancies were observed to have a higher incidence of IgG concentrations below the lower limit of the normal range (<694 mg/dL) at Month 6 than those patients who did not experience these adverse events. This observation was more pronounced with the higher than recommended dose of belatacept. A similar trend was also observed for cyclosporine-treated patients with serious infections and malignancies. - However, it is unclear whether any causal relationship between an IgG concentration below the lower level of normal and these adverse events exists, as the analysis may have been confounded by other factors (e.g., age greater than 60 years, receipt of an extended criteria donor kidney, exposure to lymphocyte depleting agents) which were also associated with IgG below the lower level of normal at Month 6 in these trials. ## Pharmacokinetics - Table 5 summarizes the pharmacokinetic parameters of belatacept in healthy adult subjects after a single 10 mg per kg intravenous infusion; and in kidney transplant patients after the 10 mg per kg intravenous infusion at Week 12, and after 5 mg per kg intravenous infusion every 4 weeks at Month 12 post-transplant or later. - In healthy subjects, the pharmacokinetics of belatacept was linear and the exposure to belatacept increased proportionally after a single intravenous infusion dose of 1 to 20 mg per kg. The pharmacokinetics of belatacept in de novo kidney transplant patients and healthy subjects are comparable. Following the recommended regimen, the mean belatacept serum concentration reached steady-state by Week 8 in the initial phase following transplantation and by Month 6 during the maintenance phase. Following once monthly intravenous infusion of 10 mg per kg and 5 mg per kg, there was about 20% and 10% systemic accumulation of belatacept in kidney transplant patients, respectively. - Based on population pharmacokinetic analysis of 924 kidney transplant patients up to 1 year post-transplant, the pharmacokinetics of belatacept were similar at different time periods post-transplant. In clinical trials, trough concentrations of belatacept were consistently maintained from Month 6 up to 3 years post-transplant. Population pharmacokinetic analyses in kidney transplant patients revealed that there was a trend toward higher clearance of belatacept with increasing body weight. Age, gender, race, renal function (measured by calculated glomerular filtration rate ), hepatic function (measured by albumin), diabetes, and concomitant dialysis did not affect the clearance of belatacept. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - A carcinogenicity study was not conducted with belatacept. However, a murine carcinogenicity study was conducted with abatacept (a more active analog in rodents) to determine the carcinogenic potential of CD28 blockade. Weekly subcutaneous injections of 20, 65, or 200 mg per kg of abatacept were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors (intermediate- and high-dose in females) at clinically relevant exposures. The mice in this study were infected with endogenous murine leukemia and mouse mammary tumor viruses which are associated with an increased incidence of lymphomas and mammary gland tumors, respectively, in immunosuppressed mice. Although the precise relevance of these findings to the clinical use of belatacept is unknown, cases of PTLD (a premalignant or malignant proliferation of B lymphocytes) were reported in clinical trials. - Genotoxicity testing is not required for protein therapeutics; therefore, no genotoxicity studies were conducted with belatacept. - Belatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg per kg daily (25 times the MRHD exposure). Animal Toxicology and/or Pharmacology - Abatacept, a fusion protein that differs from belatacept by 2 amino acids, binds to the same ligands (CD80/CD86) and blocks T-cell costimulation like belatacept, but is more active than belatacept in rodents. Therefore, toxicities identified with abatacept in rodents may be predictive of adverse effects in humans treated with belatacept. - Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (observed in juvenile rats and pregnant rats) as well as autoimmunity of the thyroid and pancreas (observed in rats exposed in utero, as juveniles or as adults). Studies of abatacept in adult mice and monkeys, as well as belatacept in adult monkeys, have not demonstrated similar findings. - The increased susceptibility to opportunistic infections observed in juvenile rats is likely associated with the exposure to abatacept before the complete development of memory immune responses. In pregnant rats, the increased susceptibility to opportunistic infections may be due to the inherent lapses in immunity that occur in rats during late pregnancy/lactation. Infections related to belatacept have been observed in human clinical trials. - Administration of abatacept to rats was associated with a significant decrease in T-regulatory cells (up to 90%). Deficiency of T-regulatory cells in humans has been associated with autoimmunity. The occurrence of autoimmune events across the core clinical trials was infrequent. However, the possibility that patients administered belatacept could develop autoimmunity (or that fetuses exposed to belatacept in utero could develop autoimmunity) cannot be excluded. - In a 6-month toxicity study with belatacept in cynomolgus monkeys administered weekly doses up to 50 mg per kg (6 times the MRHD exposure) and in a 1-year toxicity study with abatacept in adult cynomolgus monkeys administered weekly doses up to 50 mg per kg, no significant drug-related toxicities were observed. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. - Following 5 doses (10 mg per kg or 50 mg per kg, once a week for 5 weeks) of systemic administration, belatacept was not detected in brain tissue of normal healthy cynomolgus monkeys. The number of cells expressing major histocompatibility complex (MHC) class-II antigens (potential marker of immune cell activation) in the brain were increased in monkeys administered belatacept compared to vehicle control. However, distribution of some other cells expressing CD68, CD20, CD80, and CD86, typically expressed on MHC class II-positive cells, was not altered and there were no other histological changes in the brain. The clinical relevance of the findings is unknown. # Clinical Studies Prevention of Organ Rejection in Kidney Transplant Recipients - The efficacy and safety of belatacept in de novo kidney transplantation were assessed in two open-label, randomized, multicenter, active-controlled trials (Study 1 and Study 2). These trials evaluated two dose regimens of belatacept, the recommended dosage regimen and a regimen with higher cumulative doses and more frequent dosing than the recommended dosage regimen, compared to a cyclosporine control regimen. All treatment groups also received basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids. Treatment Regimen - The belatacept recommended regimen consisted of a 10 mg per kg dose administered on Day 1 (the day of transplantation, prior to implantation), Day 5 (approximately 96 hours after the Day 1 dose), end of Weeks 2 and 4; then every 4 weeks through Week 12 after transplantation. Starting at Week 16 after transplantation, belatacept was administered at the maintenance dose of 5 mg per kg every 4 weeks (plus or minus 3 days). belatacept was administered as an intravenous infusion over 30 minutes. - Basiliximab 20 mg was administered intravenously on the day of transplantation and 4 days later. - The initial dose of MMF was 1 gram twice daily and was adjusted, as needed based on clinical signs of adverse events or efficacy failure. - The protocol-specified dosing of corticosteroids in Studies 1 and 2 at Day 1 was methylprednisolone (as sodium succinate) 500 mg IV on arrival in the operating room, Day 2, methylprednisolone 250 mg IV, and Day 3, prednisone 100 mg orally. Actual median corticosteroid doses used with the belatacept recommended regimen from Week 1 through Month 6 are summarized in the table below (Table 6). - Study 1 enrolled recipients of living donor and standard criteria deceased donor organs and Study 2 enrolled recipients of extended criteria donor organs. Standard criteria donor organs were defined as organs from a deceased donor with anticipated cold ischemia time of 1.5 mg/dL); (3) donation of organ after cardiac death; or (4) anticipated cold ischemia time of the organ of ≥24 hours. Study 1 excluded recipients undergoing a first transplant whose current Panel Reactive Antibodies (PRA) were ≥50% and recipients undergoing a retransplantation whose current PRA were ≥30%; Study 2 excluded recipients with a current PRA ≥30%. Both studies excluded recipients with HIV, hepatitis C, or evidence of current hepatitis B infection; recipients with active tuberculosis; and recipients in whom intravenous access was difficult to obtain. - Efficacy data are presented for the belatacept recommended regimen and cyclosporine regimen in Studies 1 and 2. - The belatacept regimen with higher cumulative doses and more frequent dosing of belatacept was associated with more efficacy failures. Higher doses and/or more frequent dosing of belatacept are not recommended. Study 1: Recipients of Living Donor and Standard Criteria Deceased Donor Kidneys - In Study 1, 666 patients were enrolled, randomized, and transplanted: 226 to the belatacept recommended regimen, 219 to the belatacept regimen with higher cumulative doses and more frequent dosing than recommended, and 221 to cyclosporine control regimen. The median age was 45 years; 58% of organs were from living donors; 3% were re-transplanted; 69% of the study population was male; 61% of patients were white, 8% were black/African-American, 31% were categorized as of other races; 16% had PRA ≥10%; 41% had 4 to 6 HLA mismatches; and 27% had diabetes prior to transplant. The incidence of delayed graft function was similar in all treatment arms (14% to 18%). - Premature discontinuation from treatment at the end of the first year occurred in 19% of patients receiving the belatacept recommended regimen and 19% of patients on the cyclosporine regimen. Among the patients who received the belatacept recommended regimen, 10% discontinued due to lack of efficacy, 5% due to adverse events, and 4% for other reasons. Among the patients who received the cyclosporine regimen, 9% discontinued due to adverse events, 5% due to lack of efficacy, and 5% for other reasons. - At the end of three years, 25% of patients receiving the belatacept recommended regimen and 34% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the belatacept recommended regimen, 12% discontinued due to lack of efficacy, 7% due to adverse events, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 15% discontinued due to adverse events, 8% due to lack of efficacy, and 11% for other reasons. Assessment of Efficacy - Table 7 summarizes the results of Study 1 following one and three years of treatment with the NULOJIX recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed separately. - In Study 1, the rate of BPAR at one year and three years was higher in patients treated with the NULOJIX recommended regimen than the cyclosporine regimen. Of the patients who experienced BPAR with belatacept, 70% experienced BPAR by Month 3, and 84% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups (<3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups. - Patients treated with the belatacept recommended regimen experienced episodes of BPAR classified as Banff grade IIb or higher (6% at one year and 7% at three years) more frequently compared to patients treated with the cyclosporine regimen (2% at one year and 2% at three years). Also, T-cell depleting therapy was used more frequently to treat episodes of BPAR in belatacept-treated patients (10%; 23/226) compared to cyclosporine-treated patients (2%; 5/221). At Month 12, the difference in mean calculated glomerular filtration rate (GFR) between patients with and without history of BPAR was 19 mL/min/1.73 m2 among belatacept-treated patients compared to 7 mL/min/1.73 m2 among cyclosporine-treated patients. By three years, 22% (11/50) of belatacept-treated patients with a history of BPAR experienced graft loss and/or death compared to 10% (3/31) of cyclosporine-treated patients with a history of BPAR; at that time point, 10% (5/50) of belatacept-treated patients experienced graft loss and 12% (6/50) of belatacept-treated patients had died following an episode of BPAR, whereas 7% (2/31) of cyclosporine-treated patients experienced graft loss and 7% (2/31) of cyclosporine-treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 5% and 11% for the belatacept recommended regimen and cyclosporine, respectively, up to 36 months post-transplant. - While the difference in GFR in patients with BPAR versus those without BPAR was greater in patients treated with belatacept than cyclosporine, the mean GFR following BPAR was similar in belatacept (49 mL/min/1.73 m2) and cyclosporine treated patients (43 mL/min/1.73 m2) at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR. Assessment of Efficacy in the EBV Seropositive Subpopulation - Belatacept is recommended for use only in EBV seropositive patients. - In Study 1, approximately 87% of patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied. - By one year, the efficacy failure rate in the EBV seropositive population was 21% (42/202) in patients treated with the belatacept recommended regimen and 17% (31/184) in patients treated with cyclosporine (difference=4%, 97.3% CI ). Patient and graft survival was 98% (198/202) in belatacept-treated patients and 92% (170/184) in cyclosporine-treated patients (difference=5.6%, 97.3% CI ). - By three years, efficacy failure was 25% in both treatment groups and patient and graft survival was 94% (187/202) in belatacept-treated patients compared with 88% (162/184) in cyclosporine-treated patients (difference=4.6%, 97.3% CI ). Assessment of Glomerular Filtration Rate (GFR) - Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 8, both measured and calculated GFR was higher in patients treated with the belatacept recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 1, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between three and 36 months demonstrated an increase of 0.8 mL/min/year (95% CI ) for belatacept-treated patients and a decrease of 2.2 mL/min/year (95% CI ) for cyclosporine-treated patients. Assessment of Chronic Allograft Nephropathy (CAN) - The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff ’97 classification system, was 24% (54/226) in patients treated with the belatacept recommended regimen and in 32% (71/219) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown. Study 2: Recipients of Extended Criteria Donor Kidneys - In Study 2, 543 patients were enrolled, randomized, and transplanted: 175 to the belatacept recommended regimen, 184 to the belatacept regimen with higher cumulative doses and more frequent dosing than recommended, and 184 to the cyclosporine control regimen. The median age was 58 years; 67% of the study population was male; 75% of patients were white, 13% were black/African-American, 12% were categorized as of other races; 3% had PRA ≥10%; 53% had 4 to 6 HLA mismatches; and 29% had diabetes prior to transplantation. The incidence of delayed graft function was similar in all treatment arms (47% to 49%). - Premature discontinuation from treatment at the end of the first year occurred in 25% of patients receiving the belatacept recommended regimen and 30% of patients receiving the cyclosporine control regimen. Among the patients who received the belatacept recommended regimen, 14% discontinued due to adverse events, 9% due to lack of efficacy, and 2% for other reasons. Among the patients who received the cyclosporine regimen, 17% discontinued due to adverse events, 7% due to lack of efficacy, and 6% for other reasons. - At the end of three years, 35% of patients receiving the belatacept recommended regimen and 44% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the belatacept recommended regimen, 20% discontinued due to adverse events, 9% due to lack of efficacy, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 25% discontinued due to adverse events, 10% due to lack of efficacy, and 10% for other reasons. Assessment of Efficacy - Table 9 summarizes the results of Study 2 following one and three years of treatment with the belatacept recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed. - In Study 2, the rate of BPAR at one year and three years was similar in patients treated with belatacept and cyclosporine. Of the patients who experienced BPAR with belatacept, 62% experienced BPAR by Month 3, and 76% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups (<3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups. - A similar proportion of patients in the belatacept recommended regimen group experienced BPAR classified as Banff grade IIb or higher (5% at one year and 6% at three years) compared to patients treated with the cyclosporine regimen (4% at one year and 5% at three years). Also, T-cell depleting therapy was used with similar frequency to treat any episode of BPAR in belatacept-treated patients (5% or 9/175) compared to cyclosporine-treated patients (4% or 7/184). At Month 12, the difference in mean calculated GFR between patients with and without a history of BPAR was 10 mL/min/1.73 m2 among belatacept-treated patients compared to 14 mL/min/1.73 m2 among cyclosporine-treated patients. By three years, 24% (10/42) of belatacept-treated patients with a history of BPAR experienced graft loss and/or death compared to 31% (13/42) of cyclosporine-treated patients with a history of BPAR; at that time point, 17% (7/42) of belatacept-treated patients experienced graft loss and 14% (6/42) of belatacept-treated patients had died following an episode of BPAR, whereas 19% (8/42) of cyclosporine-treated patients experienced graft loss and 19% (8/42) of cyclosporine-treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 6% and 15% for the belatacept recommended regimen and cyclosporine, respectively, up to 36 months post-transplant. - The mean GFR following BPAR was 36 mL/min/1.73 m2 in belatacept patients and 24 mL/min/1.73 m2 in cyclosporine-treated patients at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR. Assessment of Efficacy in the EBV Seropositive Subpopulation - Belatacept is recommended for use only in EBV seropositive patients. - In Study 2, approximately 91% of the patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied. - By one year, the efficacy failure rate in the EBV seropositive population was 29% (45/156) in patients treated with the belatacept recommended regimen and 28% (47/168) in patients treated with cyclosporine (difference=0.8%, 97.3% CI ). Patient and graft survival rate in the EBV seropositive population was 89% (139/156) in the belatacept-treated patients and 86% (144/168) in cyclosporine-treated patients (difference=3.4%, 97.3% CI ). - By three years, efficacy failure was 35% (54/156) in belatacept-treated patients and 36% (61/168) in cyclosporine-treated patients. Patient and graft survival was 83% (130/156) in belatacept-treated patients compared with 77% (130/168) in cyclosporine-treated patients (difference=5.9%, 97.3% CI ). Assessment of Glomerular Filtration Rate (GFR) - Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 10, both measured and calculated GFR was higher in patients treated with the belatacept recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 2, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between Month 3 and Month 36 demonstrated a decrease of 0.8 mL/min/year (95% CI ) for belatacept-treated patients and a decrease of 2.0 mL/min/year (95% CI ) for cyclosporine-treated patients. Assessment of Chronic Allograft Nephropathy (CAN) - The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff ’97 classification system, was 46% (80/174) in patients treated with the belatacept recommended regimen and 52% (95/184) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown. # How Supplied - belatacept® (belatacept) lyophilized powder for intravenous infusion is supplied as a single-use vial with a silicone-free disposable syringe in the following packaging configuration: ## Storage - Belatacept lyophilized powder is stored refrigerated at 2°-8°C (36°-46°F). Protect NULOJIX from light by storing in the original package until time of use. - The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The NULOJIX infusion must be completed within 24 hours of constitution of the Belatacept lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°-8°C (36°-46°F) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20°-25°C and room light) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). Post-Transplant Lymphoproliferative Disorder - The overall risk of PTLD, especially CNS PTLD, was elevated in belatacept-treated patients. Instruct patients to immediately report any of the following neurological, cognitive, or behavioral signs and symptoms during and after therapy with belatacept: - changes in mood or usual behavior - confusion, problems thinking, loss of memory - changes in walking or talking - decreased strength or weakness on one side of the body - changes in vision Other Malignancies - Inform patients about the increased risk of malignancies, in addition to PTLD, while taking immunosuppressive therapy, especially skin cancer. Instruct patients to limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protection factor. Instruct patients to look for any signs and symptoms of skin cancer, such as suspicious moles or lesions . Progressive Multifocal Leukoencephalopathy - Cases of PML have been reported in belatacept-treated patients. Instruct patients to immediately report any of the following neurological, cognitive, or behavioral signs and symptoms during and after therapy with belatacept: - changes in mood or usual behavior - confusion, problems thinking, loss of memory - changes in walking or talking - decreased strength or weakness on one side of the body changes in vision Other Serious Infections - Inform patients about the increased risk of infection while taking immunosuppressive therapy. Instruct patients to adhere to antimicrobial prophylaxis regimens as prescribed. Tell patients to immediately report any signs and symptoms of infection during therapy with belatacept. Immunizations - Inform patients that vaccinations may be less effective while they are being treated with belatacept. Advise patients that live vaccines should be avoided. Pregnant Women and Nursing Mothers - Inform patients that belatacept has not been studied in pregnant women or nursing mothers so the effects of belatacept on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant . Instruct patients to tell their healthcare provider if they plan to breast-feed their infant. # Precautions with Alcohol - Alcohol-Belatacept interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - NULOJIX # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Belatacept Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Belatacept is an immunological agent that is FDA approved for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Adult Kidney Transplant Recipients - Belatacept is indicated for prophylaxis of organ rejection in adult patients receiving a kidney transplant. NULOJIX is to be used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids. Limitations of Use - Use belatacept only in patients who are EBV seropositive. - Use of belatacept for the prophylaxis of organ rejection in transplanted organs other than kidney has not been established. # Dosage Dosage in Adult Kidney Transplant Recipients - Belatacept should be administered in combination with basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids. In clinical trials the median (25th-75th percentile) corticosteroid doses were tapered to approximately 15 mg (10-20 mg) per day by the first 6 weeks and remained at approximately 10 mg (5-10 mg) per day for the first 6 months post-transplant. Corticosteroid utilization should be consistent with the belatacept clinical trial experience. - Due to an increased risk of post-transplant lymphoproliferative disorder (PTLD) predominantly involving the central nervous system (CNS), progressive multifocal leukoencephalopathy (PML), and serious CNS infections, administration of higher than the recommended doses or more frequent dosing of belatacept is not recommended. - Belatacept is for intravenous infusion only. Patients do not require premedication prior to administration of belatacept. - Dosing instructions are provided in Table 1. - The total infusion dose of belatacept should be based on the actual body weight of the patient at the time of transplantation, and should not be modified during the course of therapy, unless there is a change in body weight of greater than 10%. - The prescribed dose of belatacept must be evenly divisible by 12.5 mg in order for the dose to be prepared accurately using the reconstituted solution and the silicone-free disposable syringe provided. Evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100. For example: - A patient weighs 64 kg. The dose is 10 mg per kg. - Calculated Dose: 64 kg × 10 mg per kg = 640 mg - The closest doses evenly divisible by 12.5 mg below and above 640 mg are 637.5 mg and 650 mg. - The nearest dose to 640 mg is 637.5 mg. - Therefore, the actual prescribed dose for the patient should be 637.5 mg. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belatacept in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belatacept in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Belatacept in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belatacept in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belatacept in pediatric patients. # Contraindications There is limited information regarding Belatacept Contraindications in the drug label. # Warnings ## Post-Transplant Lymphoproliferative Disorder - Belatacept-treated patients have an increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared to patients on a cyclosporine-based regimen. As the total burden of immunosuppression is a risk factor for PTLD, higher than the recommended doses or more frequent dosing of belatacept and higher than recommended doses of concomitant immunosuppressive agents are not recommended. Physicians should consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms. EBV Serostatus - The risk of PTLD was higher in EBV seronegative patients compared to EBV seropositive patients. EBV seropositive patients are defined as having evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA). - Epstein-Barr virus serology should be ascertained before starting administration of belatacept, and only patients who are EBV seropositive should receive belatacept. Transplant recipients who are EBV seronegative, or with unknown serostatus, should not receive belatacept. Other Risk Factors - Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell-depleting therapy. T-cell-depleting therapies to treat acute rejection should be used cautiously. CMV prophylaxis is recommended for at least 3 months after transplantation. - Patients who are EBV seropositive and CMV seronegative may be at increased risk for PTLD compared to patients who are EBV seropositive and CMV seropositive. Since CMV seronegative patients are at increased risk for CMV disease (a known risk factor for PTLD), the clinical significance of CMV serology for PTLD remains to be determined; however, these findings should be considered when prescribing belatacept. ## Management of Immunosuppression - Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe belatacept. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient. ## Other Malignancies - Patients receiving immunosuppressants, including belatacept, are at increased risk of developing malignancies, in addition to PTLD, including the skin. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. ## Progressive Multifocal Leukoencephalopathy - Progressive multifocal leukoencephalopathy (PML) is an often rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC virus, a human polyoma virus. In clinical trials with belatacept, two cases of PML were reported in patients receiving belatacept at higher cumulative doses and more frequently than the recommended regimen, along with mycophenolate mofetil (MMF) and corticosteroids; one case occurred in a kidney transplant recipient and the second case occurred in a liver transplant recipient. As PML has been associated with high levels of overall immunosuppression, the recommended doses and frequency of belatacept and concomitant immunosuppressives, including MMF, should not be exceeded. - Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. PML is usually diagnosed by brain imaging, cerebrospinal fluid (CSF) testing for JC viral DNA by polymerase chain reaction (PCR), and/or brain biopsy. Consultation with a specialist (e.g., neurologist and/or infectious disease) should be considered for any suspected or confirmed cases of PML. - If PML is diagnosed, consideration should be given to reduction or withdrawal of immunosuppression taking into account the risk to the allograft. ## Other Serious Infections - Patients receiving immunosuppressants, including belatacept, are at increased risk of developing bacterial, viral (cytomegalovirus [CMV] and herpes), fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. - Prophylaxis for cytomegalovirus is recommended for at least 3 months after transplantation. Prophylaxis for Pneumocystis jiroveci is recommended after transplantation. Tuberculosis - Tuberculosis was more frequently observed in patients receiving belatacept than cyclosporine in clinical trials. Patients should be evaluated for tuberculosis and tested for latent infection prior to initiating belatacept. Treatment of latent tuberculosis infection should be initiated prior to belatacept use. Polyoma Virus Nephropathy - In addition to cases of JC virus-associated PML ,cases of polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, have been reported. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss . Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft. ## Liver Transplant - Use of belatacept in liver transplant patients is not recommended. In a clinical trial of liver transplant patients, use of belatacept regimens with more frequent administration of belatacept than any of those studied in kidney transplant, along with mycophenolate mofetil (MMF) and corticosteroids, was associated with a higher rate of graft loss and death compared to the tacrolimus control arms. In addition, two cases of PTLD involving the liver allograft (one fatal) and one fatal case of PML were observed among the 147 patients randomized to belatacept. The two cases of PTLD were reported among the 140 EBV seropositive patients (1.4%). The fatal case of PML was reported in a patient receiving higher than recommended doses of belatacept and MMF. ## Acute Rejection and Graft Loss with Corticosteroid Minimization - In postmarketing experience, use of belatacept in conjunction with basiliximab induction, MMF, and corticosteroid minimization to 5 mg per day between Day 3 and Week 6 post-transplant was associated with an increased rate and grade of acute rejection, particularly Grade III rejection. These Grade III rejections occurred in patients with 4 to 6 HLA mismatches. Graft loss was a consequence of Grade III rejection in some patients. - Corticosteroid utilization should be consistent with the belatacept clinical trial experience. ## Immunizations - The use of live vaccines should be avoided during treatment with belatacept, including but not limited to the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. # Adverse Reactions ## Clinical Trials Experience - The most serious adverse reactions reported with belatacept are: - PTLD, predominantly CNS PTLD, and other malignancies. - Serious infections, including JC virus-associated PML and polyoma virus nephropathy. Clinical Studies Experience - The data described below primarily derive from two randomized, active-controlled three-year trials of belatacept in de novo kidney transplant patients. In Study 1 and Study 2, belatacept was studied at the recommended dose and frequency in a total of 401 patients compared to a cyclosporine control regimen in a total of 405 patients. These two trials also included a total of 403 patients treated with a belatacept regimen of higher cumulative dose and more frequent dosing than recommended. All patients also received basiliximab induction, mycophenolate mofetil, and corticosteroids. Patients were treated and followed for 3 years. - CNS PTLD, PML, and other CNS infections were more frequently observed in association with a belatacept regimen of higher cumulative dose and more frequent dosing compared to the recommended regimen; therefore, administration of higher than the recommended doses and/or more frequent dosing of belatacept is not recommended. - The average age of patients in Studies 1 and 2 in the belatacept recommended dose and cyclosporine control regimens was 49 years, ranging from 18 to 79 years. Approximately 70% of patients were male; 67% were white, 11% were black, and 22% other races. About 25% of patients were from the United States and 75% from other countries. - Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. - The most commonly reported adverse reactions occurring in ≥20% of patients treated with the recommended dose and frequency of belatacept were anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia. - The proportion of patients who discontinued treatment due to adverse reactions was 13% for the recommended belatacept regimen and 19% for the cyclosporine control arm through three years of treatment. The most common adverse reactions leading to discontinuation in belatacept-treated patients were cytomegalovirus infection (1.5%) and complications of transplanted kidney (1.5%). - Information on selected significant adverse reactions observed during clinical trials is summarized below. Post-Transplant Lymphoproliferative Disorder - Reported cases of post-transplant lymphoproliferative disorder (PTLD) up to 36 months post transplant were obtained for belatacept by pooling both dosage regimens of belatacept in Studies 1 and 2 (804 patients) with data from a third study in kidney transplantation (Study 3, 145 patients) which evaluated two belatacept dosage regimens similar, but slightly different, from those of Studies 1 and 2 (see Table 2). The total number of belatacept patients from these three studies (949) was compared to the pooled cyclosporine control groups from all three studies (476 patients). - Among 401 patients in Studies 1 and 2 treated with the recommended regimen of belatacept and the 71 patients in Study 3 treated with a very similar (but non-identical) belatacept regimen, there were 5 cases of PTLD: 3 in EBV seropositive patients and 2 in EBV seronegative patients. Two of the 5 cases presented with CNS involvement. - Among the 477 patients in Studies 1, 2, and 3 treated with the belatacept regimen of higher cumulative dose and more frequent dosing than recommended, there were 8 cases of PTLD: 2 in EBV seropositive patients and 6 in EBV seronegative or serostatus unknown patients. Six of the 8 cases presented with CNS involvement. Therefore, administration of higher than the recommended doses or more frequent dosing of belatacept is not recommended. - One of the 476 patients treated with cyclosporine developed PTLD, without CNS involvement. - All cases of PTLD reported up to 36 months post transplant in belatacept- or cyclosporine-treated patients presented within 18 months of transplantation. - Overall, the rate of PTLD in 949 patients treated with any of the belatacept regimens was 9-fold higher in those who were EBV seronegative or EBV serostatus unknown (8/139) compared to those who were EBV seropositive (5/810 patients). Therefore belatacept is recommended for use only in patients who are EBV seropositive. EBV Seropositive Subpopulation - Among the 806 EBV seropositive patients with known CMV serostatus treated with either belatacept regimen in Studies 1, 2, and 3, two percent (2%; 4/210) of CMV seronegative patients developed PTLD compared to 0.2% (1/596) of CMV seropositive patients. Among the 404 EBV seropositive recipients treated with the recommended dosage regimen of belatacept, three PTLD cases were detected among 99 CMV seronegative patients (3%) and there was no case detected among 303 CMV seropositive patients. The clinical significance of CMV serology as a risk factor for PTLD remains to be determined; however, these findings should be considered when prescribing belatacept. Other Malignancies - Malignancies, excluding non-melanoma skin cancer and PTLD, were reported in Study 1 and Study 2 in 3.5% (14/401) of patients treated with the recommended belatacept regimen and 3.7% (15/405) of patients treated with the cyclosporine control regimen. Non-melanoma skin cancer was reported in 1.5% (6/401) of patients treated with the recommended belatacept regimen and in 3.7% (15/405) of patients treated with cyclosporine. Progressive Multifocal Leukoencephalopathy - Two fatal cases of progressive multifocal leukoencephalopathy (PML) have been reported among 1096 patients treated with a belatacept-containing regimen: one patient in clinical trials of kidney transplant (Studies 1, 2, and 3 described above) and one patient in a trial of liver transplant (trial of 250 patients). No cases of PML were reported in patients treated with the recommended belatacept regimen or the control regimen in these trials. - The kidney transplant recipient was treated with the belatacept regimen of higher cumulative dose and more frequent dosing than recommended, mycophenolate mofetil (MMF), and corticosteroids for 2 years. The liver transplant recipient was treated with 6 months of a belatacept dosage regimen that was more intensive than that studied in kidney transplant recipients, MMF at doses higher than the recommended dose, and corticosteroids. Bacterial, Mycobacterial, Viral, and Fungal Infections - Adverse reactions of infectious etiology were reported based on clinical assessment by physicians. The causative organisms for these reactions are identified when provided by the physician. The overall number of infections, serious infections, and select infections with identified etiology reported in patients treated with the belatacept recommended regimen or the cyclosporine control in Studies 1 and 2 are shown in Table 3. Fungal infections were reported in 18% of patients receiving belatacept compared to 22% receiving cyclosporine, primarily due to skin and mucocutaneous fungal infections. Tuberculosis and herpes infections were reported more frequently in patients receiving belatacept than cyclosporine. Of the patients who developed tuberculosis through 3 years, all but one belatacept patient lived in countries with a high prevalence of tuberculosis. Infections Reported in the CNS - Following three years of treatment in Studies 1 and 2, cryptococcal meningitis was reported in one patient out of 401 patients treated with the belatacept recommended regimen (0.2%) and one patient out of the 405 treated with the cyclosporine control (0.2%). - Six patients out of the 403 who were treated with the belatacept regimen of higher cumulative dose and more frequent dosing than recommended in Studies 1 and 2 (1.5%) were reported to have developed CNS infections, including 2 cases of cryptococcal meningitis, one case of Chagas encephalitis with cryptococcal meningitis, one case of cerebral aspergillosis, one case of West Nile encephalitis, and one case of PML (discussed above). Infusion Reactions - There were no reports of anaphylaxis or drug hypersensitivity in patients treated with belatacept in Studies 1 and 2 through three years. - Infusion-related reactions within one hour of infusion were reported in 5% of patients treated with the recommended dose of belatacept, similar to the placebo rate. No serious events were reported through Year 3. The most frequent reactions were hypotension and hypertension. Proteinuria - At Month 1 after transplantation in Studies 1 and 2, the frequency of 2+ proteinuria on urine dipstick in patients treated with the belatacept recommended regimen was 33% (130/390) and 28% (107/384) in patients treated with the cyclosporine control regimen. The frequency of 2+ proteinuria was similar between the two treatment groups between one and three years after transplantation (<10% in both studies). There were no differences in the occurrence of 3+ proteinuria (<4% in both studies) at any time point, and no patients experienced 4+ proteinuria. The clinical significance of this increase in early proteinuria is unknown. Immunogenicity - Antibodies directed against the belatacept molecule were assessed in 398 patients treated with the belatacept recommended regimen in Studies 1 and 2 (212 of these patients were treated for at least 2 years). Of the 372 patients with immunogenicity assessment at baseline (prior to receiving belatacept treatment), 29 patients tested positive for anti-belatacept antibodies; 13 of these patients had antibodies to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Anti-belatacept antibody titers did not increase during treatment in these 29 patients. - Eight (2%) patients developed antibodies during treatment with the belatacept recommended regimen. In the patients who developed antibodies during treatment, the median titer (by dilution method) was 8, with a range of 5 to 80. Of 56 patients who tested negative for antibodies during treatment and reassessed approximately 7 half-lives after discontinuation of belatacept, 1 tested antibody positive. Anti-belatacept antibody development was not associated with altered clearance of belatacept. - Samples from 6 patients with confirmed binding activity to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) region of the belatacept molecule were assessed by an in vitro bioassay for the presence of neutralizing antibodies. Three of these 6 patients tested positive for neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. - The clinical impact of anti-belatacept antibodies (including neutralizing anti-belatacept antibodies) could not be determined in the studies. - The data reflect the percentage of patients whose test results were positive for antibodies to belatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belatacept with the incidence of antibodies to other products may be misleading. New-Onset Diabetes After Transplantation - The incidence of new-onset diabetes after transplantation (NODAT) was defined in Studies 1 and 2 as use of an antidiabetic agent for ≥30 days or ≥2 fasting plasma glucose values ≥126 mg/dL (7.0 mmol/L) post-transplantation. Of the patients treated with the belatacept recommended regimen, 5% (14/304) developed NODAT by the end of one year compared to 10% (27/280) of patients on the cyclosporine control regimen. However, by the end of the third year, the cumulative incidence of NODAT was 8% (24/304) in patients treated with the belatacept recommended regimen and 10% (29/280) in patients treated with the cyclosporine regimen. Hypertension - Blood pressure and use of antihypertensive medications were reported in Studies 1 and 2. By Year 3, one or more antihypertensive medications were used in 85% of belatacept-treated patients and 92% of cyclosporine-treated patients. At one year after transplantation, systolic blood pressures were 8 mmHg lower and diastolic blood pressures were 3 mmHg lower in patients treated with the belatacept recommended regimen compared to the cyclosporine control regimen. At three years after transplantation, systolic blood pressures were 6 mmHg lower and diastolic blood pressures were 3 mmHg lower in belatacept-treated patients compared to cyclosporine-treated patients. Hypertension was reported as an adverse reaction in 32% of belatacept-treated patients and 37% of cyclosporine-treated patients (see Table 4). Dyslipidemia - Mean values of total cholesterol, HDL, LDL, and triglycerides were reported in Studies 1 and 2. At one year after transplantation these values were 183 mg/dL, 50 mg/dL, 102 mg/dL, and 151 mg/dL, respectively, in 401 patients treated with the belatacept recommended regimen and 196 mg/dL, 48 mg/dL, 108 mg/dL, and 195 mg/dL, respectively, in 405 patients treated with the cyclosporine control regimen. At three years after transplantation, the total cholesterol, HDL, LDL, and triglycerides were 176 mg/dL, 49 mg/dL, 100 mg/dL, and 141 mg/dL, respectively, in belatacept-treated patients compared to 193 mg/dL, 48 mg/dL, 106 mg/dL, and 180 mg/dL in cyclosporine-treated patients. - The clinical significance of the lower mean triglyceride values in belatacept-treated patients at one and three years is unknown. Other Adverse Reactions - Adverse reactions that occurred at a frequency of ≥10% in patients treated with the belatacept recommended regimen or cyclosporine control regimen in Studies 1 and 2 through three years are summarized by preferred term in decreasing order of frequency within Table 4. - Selected adverse reactions occurring in <10% from belatacept-treated patients in either regimen through three years in Studies 1 and 2 are listed below: - Immune System Disorders: Guillain-Barré syndrome - Infections and Infestations: see Table 3 - Gastrointestinal Disorders: stomatitis, including aphthous stomatitis - Injury, Poisoning, and Procedural Complications: chronic allograft nephropathy, complications of transplanted kidney, including wound dehiscence, arteriovenous fistula thrombosis - Blood and Lymphatic System Disorders: neutropenia - Renal and Urinary Disorders: renal impairment, including acute renal failure, renal artery stenosis, urinary incontinence, hydronephrosis - Vascular Disorders: hematoma, lymphocele - Musculoskeletal and Connective Tissue Disorders: musculoskeletal pain - Skin and Subcutaneous Tissue Disorders: alopecia, hyperhidrosis - Cardiac Disorders: atrial fibrillation ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Belatacept in the drug label. # Drug Interactions Mycophenolate Mofetil (MMF) - Monitor for a need to adjust concomitant mycophenolate mofetil (MMF) dosage when patient’s therapy is switched between cyclosporine and belatacept, as cyclosporine decreases mycophenolic acid (MPA) exposure by preventing enterohepatic recirculation of MPA while belatacept does not: - A higher MMF dosage may be needed after switching from belatacept to cyclosporine, since this may result in lower MPA concentrations and increase the risk of graft rejection. - A lower MMF dosage may be needed after switching from cyclosporine to belatacept, since this may result in higher MPA concentrations and increase the risk for adverse reactions related to MPA (review the Full Prescribing Information for MMF). Cytochrome P450 Substrates - No dosage adjustments are needed for drugs metabolized via CYP1A2, CYP2C9, CYP2D6, CYP3A, and CYP2C19 when coadministered with belatacept # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C - Belatacept should not be used in pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. There are no studies of belatacept treatment in pregnant women. Belatacept is known to cross the placenta of animals. Belatacept was not teratogenic in pregnant rats and rabbits at doses approximately 16 and 19 times greater than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg per kg administered over the first month of treatment, based on area under the concentration-time curve (AUC). - Belatacept administered to female rats daily during gestation and throughout the lactation period was associated with maternal toxicity (infections) in a small percentage of dams at doses of ≥20 mg per kg (≥3 times the MRHD exposure based on AUC) resulting in increased pup mortality (up to 100% pup mortality in some dams). In pups that survived, there were no abnormalities or malformations at doses up to 200 mg per kg (19 times the MRHD exposure). - In vitro data indicate that belatacept has lower binding affinity to CD80/CD86 and lower potency in rodents than in humans. Although the rat toxicity studies with belatacept were done at pharmacologically saturating doses, the in vivo difference in potency between rats and humans is unknown. Therefore, the relevance of the rat toxicities to humans and the significance of the magnitude of the relative exposures (rats: humans) are unknown. - Abatacept, a fusion protein that differs from belatacept by 2 amino acids, binds to the same ligands (CD80/CD86) and blocks T-cell costimulation like belatacept, but is more active than belatacept in rodents. Therefore, toxicities identified with abatacept in rodents, including infections and autoimmunity, may be predictive of adverse effects in humans treated with belatacept. - Autoimmunity was observed in one rat offspring exposed to abatacept in utero and/or during lactation and in juvenile rats after treatment with abatacept. However, the clinical relevance of autoimmunity in rats to patients or a fetus exposed in utero is unknown. - Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women who have received belatacept or whose partners have received belatacept, healthcare providers are strongly encouraged to register pregnant patients in the National Transplant Pregnancy Registry (NTPR) by calling 1-877-955-6877. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belatacept in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Belatacept during labor and delivery. ### Nursing Mothers - It is not known whether belatacept is excreted in human milk or absorbed systemically after ingestion by a nursing infant. However, belatacept is excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from belatacept in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - The safety and efficacy of belatacept in patients under 18 years of age have not been established. Because T cell development continues into the teenage years, the potential concern for autoimmunity in neonates applies to pediatric use as well. ### Geriatic Use - Of 401 patients treated with the recommended dosage regimen of belatacept, 15% were 65 years of age and older, while 3% were 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity or less efficacy in older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Belatacept with respect to specific gender populations. ### Race There is no FDA guidance on the use of Belatacept with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Belatacept in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Belatacept in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Belatacept in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Belatacept in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous Preparation and Administration Instructions - Belatacept is for intravenous infusion only. - Caution: NULOJIX must be reconstituted/prepared using only the silicone-free disposable syringe provided with each vial. - If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Bristol-Myers Squibb at 1-888-NULOJIX. Preparation for Administration - Calculate the number of belatacept vials required to provide the total infusion dose. Each vial contains 250 mg of belatacept lyophilized powder. - Reconstitute the contents of each vial of belatacept with 10.5 mL of a suitable diluent using the silicone-free disposable syringe provided with each vial and an 18- to 21-gauge needle. Suitable diluents include: sterile water for injection (SWFI), 0.9% sodium chloride (NS), or 5% dextrose in water (D5W). Note: If the belatacept powder is accidentally reconstituted using a different syringe than the one provided, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes. - To reconstitute the belatacept powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of diluent (10.5 mL of SWFI, NS, or D5W) to the glass wall of the vial. - To minimize foam formation, rotate the vial and invert with gentle swirling until the contents are completely dissolved. Avoid prolonged or vigorous agitation. Do not shake. - The reconstituted solution contains a belatacept concentration of 25 mg/mL and should be clear to slightly opalescent and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present. - Calculate the total volume of the reconstituted 25 mg/mL belatacept solution required to provide the total infusion dose. Volume of 25 mg/mL belatacept solution (in mL) = Prescribed Dose (in mg) ÷ 25 mg/mL - Prior to intravenous infusion, the required volume of the reconstituted belatacept solution must be further diluted with a suitable infusion fluid (NS or D5W). belatacept reconstituted with: - SWFI should be further diluted with either NS or D5W - NS should be further diluted with NS - D5W should be further diluted with D5W - From the appropriate size infusion bag or bottle, withdraw a volume of infusion fluid that is equal to the volume of the reconstituted belatacept solution required to provide the prescribed dose. With the same silicone-free disposable syringe used for reconstitution, withdraw the required amount of belatacept solution from the vial, inject it into the infusion bag or bottle, and gently rotate the infusion bag or bottle to ensure mixing. The final belatacept concentration in the infusion bag or bottle should range from 2 mg/mL to 10 mg/mL. Typically, an infusion volume of 100 mL will be appropriate for most patients and doses, but total infusion volumes ranging from 50 mL to 250 mL may be used. Any unused solution remaining in the vials must be discarded. - Prior to administration, the belatacept infusion should be inspected visually for particulate matter and discoloration. Discard the infusion if any particulate matter or discoloration is observed. - The entire belatacept infusion should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 µm). - The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The belatacept infusion must be completed within 24 hours of reconstitution of the belatacept lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°-8°C (36°-46°F) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20°-25°C [68°-77°F] and room light). - Infuse belatacept in a separate line from other concomitantly infused agents. Belatacept should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of belatacept with other agents. ### Monitoring There is limited information regarding Monitoring of Belatacept in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Belatacept in the drug label. # Overdosage - Single doses up to 20 mg per kg of NULOJIX have been administered to healthy subjects without apparent toxic effect. The administration of NULOJIX of higher cumulative dose and more frequent dosing than recommended in kidney transplant patients resulted in a higher frequency of CNS-related adverse reactions. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted # Pharmacology ## Mechanism of Action - Belatacept, a selective T-cell (lymphocyte) costimulation blocker, binds to CD80 and CD86 on antigen-presenting cells thereby blocking CD28 mediated costimulation of T lymphocytes. In vitro, belatacept inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-γ, interleukin-4, and TNF-α. Activated T lymphocytes are the predominant mediators of immunologic rejection. - In non-human primate models of renal transplantation, belatacept monotherapy prolonged graft survival and decreased the production of anti-donor antibodies, compared to vehicle. ## Structure - NULOJIX® (belatacept), a selective T-cell costimulation blocker, is a soluble fusion protein consisting of the modified extracellular domain of CTLA-4 fused to a portion (hinge-CH2-CH3 domains) of the Fc domain of a human immunoglobulin G1 antibody. Belatacept is produced by recombinant DNA technology in a mammalian cell expression system. Two amino acid substitutions (L104 to E; A29 to Y) were made in the ligand binding region of CTLA-4. As a result of these modifications, belatacept binds CD80 and CD86 more avidly than abatacept, the parent CTLA4-Immunoglobulin (CTLA4-Ig) molecule from which it is derived. The molecular weight of belatacept is approximately 90 kilodaltons. - Belatacept is supplied as a sterile, white or off-white lyophilized powder for intravenous administration. Prior to use, the lyophile is reconstituted with a suitable fluid to obtain a clear to slightly opalescent, colorless to pale yellow solution, with a pH in the range of 7.2 to 7.8. Suitable fluids for constitution of the lyophile include SWFI, 0.9% NS, or D5W . Each 250 mg single-use vial of belatacept also contains: monobasic sodium phosphate (34.5 mg), sodium chloride (5.8 mg), and sucrose (500 mg). ## Pharmacodynamics - Belatacept-mediated costimulation blockade results in the inhibition of cytokine production by T cells required for antigen-specific antibody production by B cells. In clinical trials, greater reductions in mean immunoglobulin (IgG, IgM, and IgA) concentrations were observed from baseline to Month 6 and Month 12 post-transplant in belatacept-treated patients compared to cyclosporine-treated patients. In an exploratory subset analysis, a trend of decreasing IgG concentrations with increasing belatacept trough concentrations was observed at Month 6. Also in this exploratory subset analysis, belatacept-treated patients with CNS PTLD, CNS infections including PML, other serious infections, and malignancies were observed to have a higher incidence of IgG concentrations below the lower limit of the normal range (<694 mg/dL) at Month 6 than those patients who did not experience these adverse events. This observation was more pronounced with the higher than recommended dose of belatacept. A similar trend was also observed for cyclosporine-treated patients with serious infections and malignancies. - However, it is unclear whether any causal relationship between an IgG concentration below the lower level of normal and these adverse events exists, as the analysis may have been confounded by other factors (e.g., age greater than 60 years, receipt of an extended criteria donor kidney, exposure to lymphocyte depleting agents) which were also associated with IgG below the lower level of normal at Month 6 in these trials. ## Pharmacokinetics - Table 5 summarizes the pharmacokinetic parameters of belatacept in healthy adult subjects after a single 10 mg per kg intravenous infusion; and in kidney transplant patients after the 10 mg per kg intravenous infusion at Week 12, and after 5 mg per kg intravenous infusion every 4 weeks at Month 12 post-transplant or later. - In healthy subjects, the pharmacokinetics of belatacept was linear and the exposure to belatacept increased proportionally after a single intravenous infusion dose of 1 to 20 mg per kg. The pharmacokinetics of belatacept in de novo kidney transplant patients and healthy subjects are comparable. Following the recommended regimen, the mean belatacept serum concentration reached steady-state by Week 8 in the initial phase following transplantation and by Month 6 during the maintenance phase. Following once monthly intravenous infusion of 10 mg per kg and 5 mg per kg, there was about 20% and 10% systemic accumulation of belatacept in kidney transplant patients, respectively. - Based on population pharmacokinetic analysis of 924 kidney transplant patients up to 1 year post-transplant, the pharmacokinetics of belatacept were similar at different time periods post-transplant. In clinical trials, trough concentrations of belatacept were consistently maintained from Month 6 up to 3 years post-transplant. Population pharmacokinetic analyses in kidney transplant patients revealed that there was a trend toward higher clearance of belatacept with increasing body weight. Age, gender, race, renal function (measured by calculated glomerular filtration rate [GFR]), hepatic function (measured by albumin), diabetes, and concomitant dialysis did not affect the clearance of belatacept. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - A carcinogenicity study was not conducted with belatacept. However, a murine carcinogenicity study was conducted with abatacept (a more active analog in rodents) to determine the carcinogenic potential of CD28 blockade. Weekly subcutaneous injections of 20, 65, or 200 mg per kg of abatacept were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors (intermediate- and high-dose in females) at clinically relevant exposures. The mice in this study were infected with endogenous murine leukemia and mouse mammary tumor viruses which are associated with an increased incidence of lymphomas and mammary gland tumors, respectively, in immunosuppressed mice. Although the precise relevance of these findings to the clinical use of belatacept is unknown, cases of PTLD (a premalignant or malignant proliferation of B lymphocytes) were reported in clinical trials. - Genotoxicity testing is not required for protein therapeutics; therefore, no genotoxicity studies were conducted with belatacept. - Belatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg per kg daily (25 times the MRHD exposure). Animal Toxicology and/or Pharmacology - Abatacept, a fusion protein that differs from belatacept by 2 amino acids, binds to the same ligands (CD80/CD86) and blocks T-cell costimulation like belatacept, but is more active than belatacept in rodents. Therefore, toxicities identified with abatacept in rodents may be predictive of adverse effects in humans treated with belatacept. - Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (observed in juvenile rats and pregnant rats) as well as autoimmunity of the thyroid and pancreas (observed in rats exposed in utero, as juveniles or as adults). Studies of abatacept in adult mice and monkeys, as well as belatacept in adult monkeys, have not demonstrated similar findings. - The increased susceptibility to opportunistic infections observed in juvenile rats is likely associated with the exposure to abatacept before the complete development of memory immune responses. In pregnant rats, the increased susceptibility to opportunistic infections may be due to the inherent lapses in immunity that occur in rats during late pregnancy/lactation. Infections related to belatacept have been observed in human clinical trials. - Administration of abatacept to rats was associated with a significant decrease in T-regulatory cells (up to 90%). Deficiency of T-regulatory cells in humans has been associated with autoimmunity. The occurrence of autoimmune events across the core clinical trials was infrequent. However, the possibility that patients administered belatacept could develop autoimmunity (or that fetuses exposed to belatacept in utero could develop autoimmunity) cannot be excluded. - In a 6-month toxicity study with belatacept in cynomolgus monkeys administered weekly doses up to 50 mg per kg (6 times the MRHD exposure) and in a 1-year toxicity study with abatacept in adult cynomolgus monkeys administered weekly doses up to 50 mg per kg, no significant drug-related toxicities were observed. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. - Following 5 doses (10 mg per kg or 50 mg per kg, once a week for 5 weeks) of systemic administration, belatacept was not detected in brain tissue of normal healthy cynomolgus monkeys. The number of cells expressing major histocompatibility complex (MHC) class-II antigens (potential marker of immune cell activation) in the brain were increased in monkeys administered belatacept compared to vehicle control. However, distribution of some other cells expressing CD68, CD20, CD80, and CD86, typically expressed on MHC class II-positive cells, was not altered and there were no other histological changes in the brain. The clinical relevance of the findings is unknown. # Clinical Studies Prevention of Organ Rejection in Kidney Transplant Recipients - The efficacy and safety of belatacept in de novo kidney transplantation were assessed in two open-label, randomized, multicenter, active-controlled trials (Study 1 and Study 2). These trials evaluated two dose regimens of belatacept, the recommended dosage regimen and a regimen with higher cumulative doses and more frequent dosing than the recommended dosage regimen, compared to a cyclosporine control regimen. All treatment groups also received basiliximab induction, mycophenolate mofetil (MMF), and corticosteroids. Treatment Regimen - The belatacept recommended regimen consisted of a 10 mg per kg dose administered on Day 1 (the day of transplantation, prior to implantation), Day 5 (approximately 96 hours after the Day 1 dose), end of Weeks 2 and 4; then every 4 weeks through Week 12 after transplantation. Starting at Week 16 after transplantation, belatacept was administered at the maintenance dose of 5 mg per kg every 4 weeks (plus or minus 3 days). belatacept was administered as an intravenous infusion over 30 minutes. - Basiliximab 20 mg was administered intravenously on the day of transplantation and 4 days later. - The initial dose of MMF was 1 gram twice daily and was adjusted, as needed based on clinical signs of adverse events or efficacy failure. - The protocol-specified dosing of corticosteroids in Studies 1 and 2 at Day 1 was methylprednisolone (as sodium succinate) 500 mg IV on arrival in the operating room, Day 2, methylprednisolone 250 mg IV, and Day 3, prednisone 100 mg orally. Actual median corticosteroid doses used with the belatacept recommended regimen from Week 1 through Month 6 are summarized in the table below (Table 6). - Study 1 enrolled recipients of living donor and standard criteria deceased donor organs and Study 2 enrolled recipients of extended criteria donor organs. Standard criteria donor organs were defined as organs from a deceased donor with anticipated cold ischemia time of <24 hours and not meeting the definition of extended criteria donor organs. Extended criteria donors were defined as deceased donors with at least one of the following: (1) donor age ≥60 years; (2) donor age ≥50 years and other donor comorbidities (≥2 of the following: stroke, hypertension, serum creatinine >1.5 mg/dL); (3) donation of organ after cardiac death; or (4) anticipated cold ischemia time of the organ of ≥24 hours. Study 1 excluded recipients undergoing a first transplant whose current Panel Reactive Antibodies (PRA) were ≥50% and recipients undergoing a retransplantation whose current PRA were ≥30%; Study 2 excluded recipients with a current PRA ≥30%. Both studies excluded recipients with HIV, hepatitis C, or evidence of current hepatitis B infection; recipients with active tuberculosis; and recipients in whom intravenous access was difficult to obtain. - Efficacy data are presented for the belatacept recommended regimen and cyclosporine regimen in Studies 1 and 2. - The belatacept regimen with higher cumulative doses and more frequent dosing of belatacept was associated with more efficacy failures. Higher doses and/or more frequent dosing of belatacept are not recommended. Study 1: Recipients of Living Donor and Standard Criteria Deceased Donor Kidneys - In Study 1, 666 patients were enrolled, randomized, and transplanted: 226 to the belatacept recommended regimen, 219 to the belatacept regimen with higher cumulative doses and more frequent dosing than recommended, and 221 to cyclosporine control regimen. The median age was 45 years; 58% of organs were from living donors; 3% were re-transplanted; 69% of the study population was male; 61% of patients were white, 8% were black/African-American, 31% were categorized as of other races; 16% had PRA ≥10%; 41% had 4 to 6 HLA mismatches; and 27% had diabetes prior to transplant. The incidence of delayed graft function was similar in all treatment arms (14% to 18%). - Premature discontinuation from treatment at the end of the first year occurred in 19% of patients receiving the belatacept recommended regimen and 19% of patients on the cyclosporine regimen. Among the patients who received the belatacept recommended regimen, 10% discontinued due to lack of efficacy, 5% due to adverse events, and 4% for other reasons. Among the patients who received the cyclosporine regimen, 9% discontinued due to adverse events, 5% due to lack of efficacy, and 5% for other reasons. - At the end of three years, 25% of patients receiving the belatacept recommended regimen and 34% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the belatacept recommended regimen, 12% discontinued due to lack of efficacy, 7% due to adverse events, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 15% discontinued due to adverse events, 8% due to lack of efficacy, and 11% for other reasons. Assessment of Efficacy - Table 7 summarizes the results of Study 1 following one and three years of treatment with the NULOJIX recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed separately. - In Study 1, the rate of BPAR at one year and three years was higher in patients treated with the NULOJIX recommended regimen than the cyclosporine regimen. Of the patients who experienced BPAR with belatacept, 70% experienced BPAR by Month 3, and 84% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups (<3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups. - Patients treated with the belatacept recommended regimen experienced episodes of BPAR classified as Banff grade IIb or higher (6% [14/226] at one year and 7% [15/226] at three years) more frequently compared to patients treated with the cyclosporine regimen (2% [4/221] at one year and 2% [5/221] at three years). Also, T-cell depleting therapy was used more frequently to treat episodes of BPAR in belatacept-treated patients (10%; 23/226) compared to cyclosporine-treated patients (2%; 5/221). At Month 12, the difference in mean calculated glomerular filtration rate (GFR) between patients with and without history of BPAR was 19 mL/min/1.73 m2 among belatacept-treated patients compared to 7 mL/min/1.73 m2 among cyclosporine-treated patients. By three years, 22% (11/50) of belatacept-treated patients with a history of BPAR experienced graft loss and/or death compared to 10% (3/31) of cyclosporine-treated patients with a history of BPAR; at that time point, 10% (5/50) of belatacept-treated patients experienced graft loss and 12% (6/50) of belatacept-treated patients had died following an episode of BPAR, whereas 7% (2/31) of cyclosporine-treated patients experienced graft loss and 7% (2/31) of cyclosporine-treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 5% and 11% for the belatacept recommended regimen and cyclosporine, respectively, up to 36 months post-transplant. - While the difference in GFR in patients with BPAR versus those without BPAR was greater in patients treated with belatacept than cyclosporine, the mean GFR following BPAR was similar in belatacept (49 mL/min/1.73 m2) and cyclosporine treated patients (43 mL/min/1.73 m2) at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR. Assessment of Efficacy in the EBV Seropositive Subpopulation - Belatacept is recommended for use only in EBV seropositive patients. - In Study 1, approximately 87% of patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied. - By one year, the efficacy failure rate in the EBV seropositive population was 21% (42/202) in patients treated with the belatacept recommended regimen and 17% (31/184) in patients treated with cyclosporine (difference=4%, 97.3% CI [−4.8, 12.8]). Patient and graft survival was 98% (198/202) in belatacept-treated patients and 92% (170/184) in cyclosporine-treated patients (difference=5.6%, 97.3% CI [0.8, 10.4]). - By three years, efficacy failure was 25% in both treatment groups and patient and graft survival was 94% (187/202) in belatacept-treated patients compared with 88% (162/184) in cyclosporine-treated patients (difference=4.6%, 97.3% CI [−2.1, 11.3]). Assessment of Glomerular Filtration Rate (GFR) - Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 8, both measured and calculated GFR was higher in patients treated with the belatacept recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 1, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between three and 36 months demonstrated an increase of 0.8 mL/min/year (95% CI [−0.2, 1.8]) for belatacept-treated patients and a decrease of 2.2 mL/min/year (95% CI [−3.2, −1.2]) for cyclosporine-treated patients. Assessment of Chronic Allograft Nephropathy (CAN) - The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff ’97 classification system, was 24% (54/226) in patients treated with the belatacept recommended regimen and in 32% (71/219) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown. Study 2: Recipients of Extended Criteria Donor Kidneys - In Study 2, 543 patients were enrolled, randomized, and transplanted: 175 to the belatacept recommended regimen, 184 to the belatacept regimen with higher cumulative doses and more frequent dosing than recommended, and 184 to the cyclosporine control regimen. The median age was 58 years; 67% of the study population was male; 75% of patients were white, 13% were black/African-American, 12% were categorized as of other races; 3% had PRA ≥10%; 53% had 4 to 6 HLA mismatches; and 29% had diabetes prior to transplantation. The incidence of delayed graft function was similar in all treatment arms (47% to 49%). - Premature discontinuation from treatment at the end of the first year occurred in 25% of patients receiving the belatacept recommended regimen and 30% of patients receiving the cyclosporine control regimen. Among the patients who received the belatacept recommended regimen, 14% discontinued due to adverse events, 9% due to lack of efficacy, and 2% for other reasons. Among the patients who received the cyclosporine regimen, 17% discontinued due to adverse events, 7% due to lack of efficacy, and 6% for other reasons. - At the end of three years, 35% of patients receiving the belatacept recommended regimen and 44% of patients receiving the cyclosporine regimen had discontinued from treatment. Among the patients who received the belatacept recommended regimen, 20% discontinued due to adverse events, 9% due to lack of efficacy, and 6% for other reasons. Among the patients who received the cyclosporine regimen, 25% discontinued due to adverse events, 10% due to lack of efficacy, and 10% for other reasons. Assessment of Efficacy - Table 9 summarizes the results of Study 2 following one and three years of treatment with the belatacept recommended dosage regimen and the cyclosporine control regimen. Efficacy failure at one year was defined as the occurrence of biopsy proven acute rejection (BPAR), graft loss, death, or lost to follow-up. BPAR was defined as histologically confirmed acute rejection by a central pathologist on a biopsy done for any reason, whether or not accompanied by clinical signs of rejection. Patient and graft survival was also assessed. - In Study 2, the rate of BPAR at one year and three years was similar in patients treated with belatacept and cyclosporine. Of the patients who experienced BPAR with belatacept, 62% experienced BPAR by Month 3, and 76% experienced BPAR by Month 6. By three years, recurrent BPAR occurred with similar frequency across treatment groups (<3%). The component of BPAR determined by biopsy only (subclinical protocol-defined acute rejection) was 5% in both treatment groups. - A similar proportion of patients in the belatacept recommended regimen group experienced BPAR classified as Banff grade IIb or higher (5% [9/175] at one year and 6% [10/175] at three years) compared to patients treated with the cyclosporine regimen (4% [7/184] at one year and 5% [9/184] at three years). Also, T-cell depleting therapy was used with similar frequency to treat any episode of BPAR in belatacept-treated patients (5% or 9/175) compared to cyclosporine-treated patients (4% or 7/184). At Month 12, the difference in mean calculated GFR between patients with and without a history of BPAR was 10 mL/min/1.73 m2 among belatacept-treated patients compared to 14 mL/min/1.73 m2 among cyclosporine-treated patients. By three years, 24% (10/42) of belatacept-treated patients with a history of BPAR experienced graft loss and/or death compared to 31% (13/42) of cyclosporine-treated patients with a history of BPAR; at that time point, 17% (7/42) of belatacept-treated patients experienced graft loss and 14% (6/42) of belatacept-treated patients had died following an episode of BPAR, whereas 19% (8/42) of cyclosporine-treated patients experienced graft loss and 19% (8/42) of cyclosporine-treated patients had died following an episode of BPAR. The overall prevalence of donor-specific antibodies was 6% and 15% for the belatacept recommended regimen and cyclosporine, respectively, up to 36 months post-transplant. - The mean GFR following BPAR was 36 mL/min/1.73 m2 in belatacept patients and 24 mL/min/1.73 m2 in cyclosporine-treated patients at one year. The relationship between BPAR, GFR, and patient and graft survival is unclear due to the limited number of patients who experienced BPAR, differences in renal hemodynamics (and, consequently, GFR) across maintenance immunosuppression regimens, and the high rate of switching treatment regimens after BPAR. Assessment of Efficacy in the EBV Seropositive Subpopulation - Belatacept is recommended for use only in EBV seropositive patients. - In Study 2, approximately 91% of the patients were EBV seropositive prior to transplant. Efficacy results in the EBV seropositive subpopulation were consistent with those in the total population studied. - By one year, the efficacy failure rate in the EBV seropositive population was 29% (45/156) in patients treated with the belatacept recommended regimen and 28% (47/168) in patients treated with cyclosporine (difference=0.8%, 97.3% CI [−10.3, 11.9]). Patient and graft survival rate in the EBV seropositive population was 89% (139/156) in the belatacept-treated patients and 86% (144/168) in cyclosporine-treated patients (difference=3.4%, 97.3% CI [−4.7, 11.5]). - By three years, efficacy failure was 35% (54/156) in belatacept-treated patients and 36% (61/168) in cyclosporine-treated patients. Patient and graft survival was 83% (130/156) in belatacept-treated patients compared with 77% (130/168) in cyclosporine-treated patients (difference=5.9%, 97.3% CI [−3.8, 15.6]). Assessment of Glomerular Filtration Rate (GFR) - Glomerular Filtration Rate (GFR) was measured at one and two years and was calculated using the Modification of Diet in Renal Disease (MDRD) formula at one, two, and three years after transplantation. As shown in Table 10, both measured and calculated GFR was higher in patients treated with the belatacept recommended regimen compared to patients treated with the cyclosporine control regimen at all time points. As shown in Figure 2, the differences in GFR were apparent in the first month after transplant and were maintained up to three years (36 months). An analysis of change of calculated mean GFR between Month 3 and Month 36 demonstrated a decrease of 0.8 mL/min/year (95% CI [−1.9, 0.3]) for belatacept-treated patients and a decrease of 2.0 mL/min/year (95% CI [−3.1, −0.8]) for cyclosporine-treated patients. Assessment of Chronic Allograft Nephropathy (CAN) - The prevalence of chronic allograft nephropathy (CAN) at one year, as defined by the Banff ’97 classification system, was 46% (80/174) in patients treated with the belatacept recommended regimen and 52% (95/184) of patients treated with the cyclosporine control regimen. CAN was not evaluated after the first year following transplantation. The clinical significance of this finding is unknown. # How Supplied - belatacept® (belatacept) lyophilized powder for intravenous infusion is supplied as a single-use vial with a silicone-free disposable syringe in the following packaging configuration: ## Storage - Belatacept lyophilized powder is stored refrigerated at 2°-8°C (36°-46°F). Protect NULOJIX from light by storing in the original package until time of use. - The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The NULOJIX infusion must be completed within 24 hours of constitution of the Belatacept lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°-8°C (36°-46°F) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature: 20°-25°C [68°-77°F] and room light) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). Post-Transplant Lymphoproliferative Disorder - The overall risk of PTLD, especially CNS PTLD, was elevated in belatacept-treated patients. Instruct patients to immediately report any of the following neurological, cognitive, or behavioral signs and symptoms during and after therapy with belatacept: - changes in mood or usual behavior - confusion, problems thinking, loss of memory - changes in walking or talking - decreased strength or weakness on one side of the body - changes in vision Other Malignancies - Inform patients about the increased risk of malignancies, in addition to PTLD, while taking immunosuppressive therapy, especially skin cancer. Instruct patients to limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protection factor. Instruct patients to look for any signs and symptoms of skin cancer, such as suspicious moles or lesions [see WARNINGS AND PRECAUTIONS (5.3)]. Progressive Multifocal Leukoencephalopathy - Cases of PML have been reported in belatacept-treated patients. Instruct patients to immediately report any of the following neurological, cognitive, or behavioral signs and symptoms during and after therapy with belatacept: - changes in mood or usual behavior - confusion, problems thinking, loss of memory - changes in walking or talking - decreased strength or weakness on one side of the body changes in vision Other Serious Infections - Inform patients about the increased risk of infection while taking immunosuppressive therapy. Instruct patients to adhere to antimicrobial prophylaxis regimens as prescribed. Tell patients to immediately report any signs and symptoms of infection during therapy with belatacept. Immunizations - Inform patients that vaccinations may be less effective while they are being treated with belatacept. Advise patients that live vaccines should be avoided. Pregnant Women and Nursing Mothers - Inform patients that belatacept has not been studied in pregnant women or nursing mothers so the effects of belatacept on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant . Instruct patients to tell their healthcare provider if they plan to breast-feed their infant. # Precautions with Alcohol - Alcohol-Belatacept interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - NULOJIX # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Belatacept
41dbfd092e573dc2ae753db7f0fb4eb0e2cc5ce2	wikidoc	Belinostat	Belinostat # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Belinostat is an antineoplastic agent that is FDA approved for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).. Common adverse reactions include nausea, fatigue, pyrexia, anemia, and vomiting, pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Belinostat is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). - This indication is approved under accelerated approval based on tumor response rate and duration of response . An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. ### Dosing Information - The recommended dosage of Belinostat is 1,000 mg/m2 administered over 30 minutes by intravenous infusion once daily on Days 1-5 of a 21-day cycle. Cycles can be repeated every 21 days until disease progression or unacceptable toxicity. - Table 1 displays the recommended Belinostat dosage modifications for hematologic and non-hematologic toxicities. Base dosage adjustments for thrombocytopenia and neutropenia on platelet and absolute neutrophil nadir (lowest value) counts in the preceding cycle of therapy. - Absolute neutrophil count (ANC) should be greater than or equal to 1.0 x 10 9/L and the platelet count should be greater than or equal to 50 x 10 9/L prior to the start of each cycle and prior to resuming treatment following toxicity. Resume subsequent treatment with Belinostat according to the guidelines described in Table 1 below. Discontinue Belinostat in patients who have recurrent ANC nadirs less than 0.5 x 10 9/L and/or recurrent platelet count nadirs less than 25 x 10 9/L after two dosage reductions. - Other toxicities must be NCI-CTCAE Grade 2 or less prior to re-treatment. - Monitor complete blood counts at baseline and weekly. Perform serum chemistry tests, including renal and hepatic functions prior to the start of the first dose of each cycle. - Reduce the starting dose of Belinostat to 750 mg/m2 in patients known to be homozygous for the UGT1A128 allele. - As with other potentially cytotoxic anticancer agents, exercise care in the handling and preparation of solutions prepared with Belinostat . - Aseptically reconstitute each vial of Belinostat by adding 9 mL of Sterile Water for injection, USP, into the Belinostat vial with a suitable syringe to achieve a concentration of 50 mg of belinostat per mL. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted product may be stored for up to 12 hours at ambient temperature (15-25°C; 59-77°F). - Aseptically withdraw the volume needed for the required dosage (based on the 50 mg/mL concentration and the patient’s BSA ) and transfer to an infusion bag containing 250 mL of 0.9 % Sodium Chloride injection. The infusion bag with drug solution may be stored at ambient room temperature (15-25°C; 59-77°F) for up to 36 hours including infusion time. - Visually inspect the solution for particulate matter. Do not use if cloudiness or particulates are observed. - Connect the infusion bag containing drug solution to an infusion set with a 0.22 µm in-line filter for administration. - Infuse intravenously over 30 minutes. If infusion site pain or other symptoms potentially attributable to the infusion occur, the infusion time may be extended to 45 minutes. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belinostat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belinostat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Belinostat FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belinostat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belinostat in pediatric patients. # Contraindications - None. # Warnings - Belinostat can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary . - Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Belinostat . Do not administer Belinostat to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections. - Belinostat can cause fatal hepatotoxicity and liver function test abnormalities . Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Belinostat based on the severity of the hepatic toxicity - Tumor lysis syndrome has occurred in Belinostat -treated patients in the clinical trial of patients with relapsed or refractory PTCL . Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions . - Nausea, vomiting and diarrhea occur with Belinostat and may require the use of antiemetic and antidiarrheal medications. - Belinostat can cause fetal harm when administered to a pregnant woman. Belinostat may cause teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing cells . Women of childbearing potential should be advised to avoid pregnancy while receiving Belinostat . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are described in more detail in other sections of the prescribing information. - Hematologic Toxicity - Infection - Hepatotoxicity - Tumor Lysis Syndrome - Gastrointestinal Toxicity - The most common adverse reactions observed in the trial of patients with relapsed or refractory PTCL treated with Belinostat were nausea, fatigue, pyrexia, anemia, and vomiting . - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Belinostat may not reflect the rates observed in practice. - The safety of Belinostat was evaluated in 129 patients with relapsed or refractory PTCL in the single arm clinical trial in which patients were administered Belinostat at a dosage of 1,000 mg/m2 administered over 30 minutes by IV infusion once daily on Days 1-5 of a 21-day cycle . The median duration of treatment was 2 cycles (range 1 – 33 cycles). Table 2 summarizes the adverse reactions regardless of causality from the trial in patients with relapsed or refractory PTCL. Note: Adverse reactions are listed by order of incidence in the “All Grades” category first, then by incidence in “the Grade 3 or 4” category; MedDRA = Medical Dictionary for Regulatory Activities; Severity measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 - Sixty-one patients (47.3%) experienced serious adverse reactions while taking Belinostat or within 30 days after their last dose of Belinostat . The most common serious adverse reactions (> 2%) were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure. One treatment-related death associated with hepatic failure was reported in the trial. - One patient with baseline hyperuricemia and bulky disease experienced Grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multi-organ failure. A treatment-related death from ventricular fibrillation was reported in another monotherapy clinical trial with Belinostat . ECG analysis did not identify QTc prolongation. - Twenty-five patients (19.4%) discontinued treatment with Belinostat due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment included anemia, febrile neutropenia, fatigue, and multi-organ failure. - In the trial, dosage adjustments due to adverse reactions occurred in 12% of Belinostat -treated patients. There is limited information regarding Clinical Trial Experience of Belinostat in the drug label. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Belinostat in the drug label. # Drug Interactions - Belinostat is primarily metabolized by UGT1A1. Avoid concomitant administration of Belinostat with strong inhibitors of UGT1A1 . - Co-administration of Belinostat and warfarin resulted in no clinically relevant increase in plasma exposure of either R-warfarin or S-warfarin that would require a dose adjustment # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Belinostat may cause teratogenicity and/or embryo-fetal lethality because it is a genotoxic drug and targets actively dividing cells . Women should avoid pregnancy while receiving Belinostat . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus. - No reproductive and developmental animal toxicology studies have been conducted with belinostat. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belinostat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Belinostat during labor and delivery. ### Nursing Mothers - It is not known whether belinostat is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Belinostat , a decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Pediatric patients were not included in clinical trials. The safety and effectiveness of Belinostat in pediatric patients have not been established. ### Geriatic Use - In the single-arm trial, 48% of patients (n = 62) were ≥ 65 years of age and 10% of patients (n=13) were ≥ 75 years of age . The median age of the trial population was 63 years. Patients ≥ 65 years of age had a higher response rate to Belinostat treatment than patients < 65 years of age (36% versus 16%) while no meaningful differences in response rate were observed between patients ≥ 75 years of age and those < 75 years of age. No clinically meaningful differences in serious adverse reactions were observed in patients based on age (< 65 years compared with ≥ 65 years or < 75 years of age compared with ≥ 75 years of age). ### Gender There is no FDA guidance on the use of Belinostat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Belinostat with respect to specific racial populations. ### Renal Impairment - Approximately 40% of the belinostat dose is excreted renally, primarily as metabolites. Belinostat exposure is not altered in patients with Creatinine Clearance (CLcr) > 39 mL/min. There is insufficient data to recommend a dose of Belinostat in patients with CLcr ≤ 39 mL/min. ### Hepatic Impairment - Belinostat is metabolized in the liver and hepatic impairment is expected to increase exposure to belinostat. Patients with moderate and severe hepatic impairment (total bilirubin >1.5 x upper limit of normal (ULN)) were excluded from clinical trials. There is insufficient data to recommend a dose of Belinostat in patients with moderate and severe hepatic impairment ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Belinostat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Belinostat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Belinostat can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary. # IV Compatibility There is limited information regarding IV Compatibility of Belinostat in the drug label. # Overdosage - No specific information is available on the treatment of overdosage of Belinostat . There is no antidote for Belinostat and it is not known if Belinostat is dialyzable. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. The elimination half-life of belinostat is 1.1 hours # Pharmacology ## Mechanism of Action - Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations (<250 nM). ## Structure - Belinostat is a histone deacetylase inhibitor with a sulfonamide-hydroxamide structure. The chemical name of belinostat is (2E)-N-hydroxy-3-prop-2-enamide. The structural formula is as follows: The molecular formula is C15H14N2O4S and the molecular weight is 318.35 g/mol. - Belinostat is a white to off-white powder. It is slightly soluble in distilled water (0.14 mg/mL) and polyethylene glycol 400 (about 1.5 mg/mL), and is freely soluble in ethanol (> 200 mg/mL). The pKa values are 7.87 and 8.71 by potentiometry and 7.86 and 8.59 by UV. - Belinostat (belinostat) for injection is supplied as a sterile lyophilized yellow powder containing 500 mg belinostat as the active ingredient. Each vial also contains 1000 mg L-Arginine, USP as an inactive ingredient. The drug product is supplied in a single-use 30 mL clear glass vial with a coated stopper and aluminum crimp seal with “flip-off” cap. Belinostat is intended for intravenous administration after reconstitution with 9 mL Sterile Water for injection, and the reconstituted solution is further diluted with 250 mL of sterile 0.9% Sodium Chloride injection prior to infusion ## Pharmacodynamics - Multiple clinical trials have been conducted with Belinostat , in many of which ECG data were collected and analyzed by a central laboratory. Analysis of clinical ECG and belinostat plasma concentration data demonstrated no meaningful effect of Belinostat on cardiac repolarization. None of the trials showed any clinically relevant changes caused by Belinostat on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes. ## Pharmacokinetics - The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase 1/2 clinical studies that used doses of belinostat ranging from 150 to 1200 mg/m2. The total mean plasma clearance and elimination half-life were 1240 mL/min and 1.1 hours, respectively. The total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic extraction (clearance being flow dependent). - The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution. In vitro plasma studies have shown that between 92.9% and 95.8% of belinostat is bound to protein in an equilibrium dialysis assay, and was independent of belinostat plasma concentrations from 500 to 25,000 ng/mL. - Belinostat is primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known. - Belinostat is eliminated predominantly through metabolism with less than 2% of the dose recovered unchanged in urine. All major human metabolites (methyl belinostat, belinostat amide, belinostat acid, belinostat glucuronide, and 3-ASBA) are generally excreted in urine within the first 24 hours after dose administration. Metabolites 3-ASBA and belinostat glucuronide represented the highest fractions of the belinostat dose excreted in urine (4.61% and 30.5%, respectively). - In vitro studies showed belinostat and its metabolites (including belinostat glucuronide, belinostat amide, methyl belinostat) inhibited metabolic activities of CYP2C8 and CYP2C9. Other metabolites (3-ASBA and belinostat acid) inhibited CYP2C8. - In cancer patients, co-administration of Belinostat (1,000 mg/m2) and warfarin (5 mg), a known CYP2C9 substrate, did not increase the AUC or Cmax of either R- or S-warfarin. - Belinostat is likely a glycoprotein (P-gp) substrate but is unlikely to inhibit P-gp. - UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A128 polymorphism. Approximately 20% of the black population, 10% of the white population, and 2% of the Asian population are homozygous for the UGT1A128 allele. Additional reduced function alleles may be more prevalent in specific populations. - Because belinostat is primarily (80 -90%) metabolized by UGT1A1, the clearance of belinostat could be decreased in patients with reduced UGT1A1 activity (e.g., patients with UGT1A128 allele). Reduce the starting dose of Belinostat to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele to minimize dose limiting toxicities. ## Nonclinical Toxicology - Carcinogenicity studies have not been performed with belinostat. - Belinostat was genotoxic in a bacterial reverse mutation test (Ames assay), an in vitro mouse lymphoma cell mutagenesis assay, and an in vivo rat micronucleus assay. - Belinostat may impair male fertility. Fertility studies using belinostat were not conducted. However, belinostat effects on male reproductive organs observed during the 24-week repeat-dose dog toxicology study included reduced organ weights of the testes/epididymides that correlated with a delay in testicular maturation # Clinical Studies - In an open-label, single-arm, non-randomized international trial conducted at 62 centers, 129 patients with relapsed or refractory PTCL were treated with Belinostat 1,000 mg/m2 administered over 30 minutes via IV infusion once daily on Days 1-5 of a 21-day cycle. There were 120 patients who had histologically confirmed PTCL by central review evaluable for efficacy. Patients were treated with repeat cycles every three weeks until disease progression or unacceptable toxicity. - The primary efficacy endpoint was response rate (complete response and partial response) as assessed by an independent review committee (IRC) using the International Workshop Criteria (IWC) (Cheson 2007). The key secondary efficacy endpoint was duration of response. Response assessments were evaluated every 6 weeks for the first 12 months and then every 12 weeks until 2 years from the start of study treatment. Duration of response was measured from the first day of documented response to disease progression or death. Response and progression of disease were evaluated by the IRC using the IWC. - Table 3 summarizes the baseline demographic and disease characteristics of the study population, who were evaluable for efficacy. - The median duration of response based on the first date of response to disease progression or death was 8.4 months (95% CI: 4.5 – 29.4). Of the responders, the median time to response was 5.6 weeks (range 4.3 - 50.4 weeks). Nine patients (7.5%) were able to proceed to a stem cell transplant after treatment with Belinostat . # How Supplied - Belinostat (belinostat) for injection is supplied in single vial cartons; each 30 mL clear vial contains sterile, lyophilized powder equivalent to 500 mg belinostat. - NDC 68152-108-09: Individual carton of Belinostat 30 mL single-use vial containing 500 mg belinostat. ## Storage - Store Belinostat (belinostat) for injection at room temperature 20°C to 25°C (68°C to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). Retain in original package until use. . - Belinostat is a cytotoxic drug. Follow special handling and disposal procedures # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Physicians should discuss the FDA approved Patient Information Leaflet with patients prior to treatment with Belinostat . Instruct patients to read the Patient Information Leaflet carefully. - Advise the patient or the caregiver to read the FDA-approved patient labeling (Patient Information). - Advise patients or their caregivers: - To report symptoms of nausea, vomiting and diarrhea so that appropriate antiemetic and antidiarrheal medications can be administered - To report any symptoms of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia . - To immediately report symptoms of infection (e.g., pyrexia) . - Of the potential risk to the fetus and for women to avoid pregnancy while receiving Belinostat . - To understand the importance of monitoring liver function test abnormalities and to immediately report potential symptoms of liver injury # Precautions with Alcohol - Alcohol-Belinostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Belinostat ® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Belinostat Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Belinostat is an antineoplastic agent that is FDA approved for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).. Common adverse reactions include nausea, fatigue, pyrexia, anemia, and vomiting, pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Belinostat is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). - This indication is approved under accelerated approval based on tumor response rate and duration of response . An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. ### Dosing Information - The recommended dosage of Belinostat is 1,000 mg/m2 administered over 30 minutes by intravenous infusion once daily on Days 1-5 of a 21-day cycle. Cycles can be repeated every 21 days until disease progression or unacceptable toxicity. - Table 1 displays the recommended Belinostat dosage modifications for hematologic and non-hematologic toxicities. Base dosage adjustments for thrombocytopenia and neutropenia on platelet and absolute neutrophil nadir (lowest value) counts in the preceding cycle of therapy. - Absolute neutrophil count (ANC) should be greater than or equal to 1.0 x 10 9/L and the platelet count should be greater than or equal to 50 x 10 9/L prior to the start of each cycle and prior to resuming treatment following toxicity. Resume subsequent treatment with Belinostat according to the guidelines described in Table 1 below. Discontinue Belinostat in patients who have recurrent ANC nadirs less than 0.5 x 10 9/L and/or recurrent platelet count nadirs less than 25 x 10 9/L after two dosage reductions. - Other toxicities must be NCI-CTCAE Grade 2 or less prior to re-treatment. - Monitor complete blood counts at baseline and weekly. Perform serum chemistry tests, including renal and hepatic functions prior to the start of the first dose of each cycle. - Reduce the starting dose of Belinostat to 750 mg/m2 in patients known to be homozygous for the UGT1A128 allele. - As with other potentially cytotoxic anticancer agents, exercise care in the handling and preparation of solutions prepared with Belinostat . - Aseptically reconstitute each vial of Belinostat by adding 9 mL of Sterile Water for injection, USP, into the Belinostat vial with a suitable syringe to achieve a concentration of 50 mg of belinostat per mL. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted product may be stored for up to 12 hours at ambient temperature (15-25°C; 59-77°F). - Aseptically withdraw the volume needed for the required dosage (based on the 50 mg/mL concentration and the patient’s BSA [m 2]) and transfer to an infusion bag containing 250 mL of 0.9 % Sodium Chloride injection. The infusion bag with drug solution may be stored at ambient room temperature (15-25°C; 59-77°F) for up to 36 hours including infusion time. - Visually inspect the solution for particulate matter. Do not use if cloudiness or particulates are observed. - Connect the infusion bag containing drug solution to an infusion set with a 0.22 µm in-line filter for administration. - Infuse intravenously over 30 minutes. If infusion site pain or other symptoms potentially attributable to the infusion occur, the infusion time may be extended to 45 minutes. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belinostat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belinostat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Belinostat FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belinostat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belinostat in pediatric patients. # Contraindications - None. # Warnings - Belinostat can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary . - Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Belinostat . Do not administer Belinostat to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections. - Belinostat can cause fatal hepatotoxicity and liver function test abnormalities . Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Belinostat based on the severity of the hepatic toxicity - Tumor lysis syndrome has occurred in Belinostat -treated patients in the clinical trial of patients with relapsed or refractory PTCL . Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions . - Nausea, vomiting and diarrhea occur with Belinostat and may require the use of antiemetic and antidiarrheal medications. - Belinostat can cause fetal harm when administered to a pregnant woman. Belinostat may cause teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing cells . Women of childbearing potential should be advised to avoid pregnancy while receiving Belinostat . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are described in more detail in other sections of the prescribing information. - Hematologic Toxicity - Infection - Hepatotoxicity - Tumor Lysis Syndrome - Gastrointestinal Toxicity - The most common adverse reactions observed in the trial of patients with relapsed or refractory PTCL treated with Belinostat were nausea, fatigue, pyrexia, anemia, and vomiting . - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Belinostat may not reflect the rates observed in practice. - The safety of Belinostat was evaluated in 129 patients with relapsed or refractory PTCL in the single arm clinical trial in which patients were administered Belinostat at a dosage of 1,000 mg/m2 administered over 30 minutes by IV infusion once daily on Days 1-5 of a 21-day cycle . The median duration of treatment was 2 cycles (range 1 – 33 cycles). Table 2 summarizes the adverse reactions regardless of causality from the trial in patients with relapsed or refractory PTCL. Note: Adverse reactions are listed by order of incidence in the “All Grades” category first, then by incidence in “the Grade 3 or 4” category; MedDRA = Medical Dictionary for Regulatory Activities; Severity measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 - Sixty-one patients (47.3%) experienced serious adverse reactions while taking Belinostat or within 30 days after their last dose of Belinostat . The most common serious adverse reactions (> 2%) were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure. One treatment-related death associated with hepatic failure was reported in the trial. - One patient with baseline hyperuricemia and bulky disease experienced Grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multi-organ failure. A treatment-related death from ventricular fibrillation was reported in another monotherapy clinical trial with Belinostat . ECG analysis did not identify QTc prolongation. - Twenty-five patients (19.4%) discontinued treatment with Belinostat due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment included anemia, febrile neutropenia, fatigue, and multi-organ failure. - In the trial, dosage adjustments due to adverse reactions occurred in 12% of Belinostat -treated patients. There is limited information regarding Clinical Trial Experience of Belinostat in the drug label. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Belinostat in the drug label. # Drug Interactions - Belinostat is primarily metabolized by UGT1A1. Avoid concomitant administration of Belinostat with strong inhibitors of UGT1A1 . - Co-administration of Belinostat and warfarin resulted in no clinically relevant increase in plasma exposure of either R-warfarin or S-warfarin that would require a dose adjustment # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Belinostat may cause teratogenicity and/or embryo-fetal lethality because it is a genotoxic drug and targets actively dividing cells . Women should avoid pregnancy while receiving Belinostat . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus. - No reproductive and developmental animal toxicology studies have been conducted with belinostat. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belinostat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Belinostat during labor and delivery. ### Nursing Mothers - It is not known whether belinostat is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Belinostat , a decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Pediatric patients were not included in clinical trials. The safety and effectiveness of Belinostat in pediatric patients have not been established. ### Geriatic Use - In the single-arm trial, 48% of patients (n = 62) were ≥ 65 years of age and 10% of patients (n=13) were ≥ 75 years of age . The median age of the trial population was 63 years. Patients ≥ 65 years of age had a higher response rate to Belinostat treatment than patients < 65 years of age (36% versus 16%) while no meaningful differences in response rate were observed between patients ≥ 75 years of age and those < 75 years of age. No clinically meaningful differences in serious adverse reactions were observed in patients based on age (< 65 years compared with ≥ 65 years or < 75 years of age compared with ≥ 75 years of age). ### Gender There is no FDA guidance on the use of Belinostat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Belinostat with respect to specific racial populations. ### Renal Impairment - Approximately 40% of the belinostat dose is excreted renally, primarily as metabolites. Belinostat exposure is not altered in patients with Creatinine Clearance (CLcr) > 39 mL/min. There is insufficient data to recommend a dose of Belinostat in patients with CLcr ≤ 39 mL/min. ### Hepatic Impairment - Belinostat is metabolized in the liver and hepatic impairment is expected to increase exposure to belinostat. Patients with moderate and severe hepatic impairment (total bilirubin >1.5 x upper limit of normal (ULN)) were excluded from clinical trials. There is insufficient data to recommend a dose of Belinostat in patients with moderate and severe hepatic impairment ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Belinostat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Belinostat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Belinostat can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary. # IV Compatibility There is limited information regarding IV Compatibility of Belinostat in the drug label. # Overdosage - No specific information is available on the treatment of overdosage of Belinostat . There is no antidote for Belinostat and it is not known if Belinostat is dialyzable. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. The elimination half-life of belinostat is 1.1 hours # Pharmacology ## Mechanism of Action - Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations (<250 nM). ## Structure - Belinostat is a histone deacetylase inhibitor with a sulfonamide-hydroxamide structure. The chemical name of belinostat is (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide. The structural formula is as follows: The molecular formula is C15H14N2O4S and the molecular weight is 318.35 g/mol. - Belinostat is a white to off-white powder. It is slightly soluble in distilled water (0.14 mg/mL) and polyethylene glycol 400 (about 1.5 mg/mL), and is freely soluble in ethanol (> 200 mg/mL). The pKa values are 7.87 and 8.71 by potentiometry and 7.86 and 8.59 by UV. - Belinostat (belinostat) for injection is supplied as a sterile lyophilized yellow powder containing 500 mg belinostat as the active ingredient. Each vial also contains 1000 mg L-Arginine, USP as an inactive ingredient. The drug product is supplied in a single-use 30 mL clear glass vial with a coated stopper and aluminum crimp seal with “flip-off” cap. Belinostat is intended for intravenous administration after reconstitution with 9 mL Sterile Water for injection, and the reconstituted solution is further diluted with 250 mL of sterile 0.9% Sodium Chloride injection prior to infusion ## Pharmacodynamics - Multiple clinical trials have been conducted with Belinostat , in many of which ECG data were collected and analyzed by a central laboratory. Analysis of clinical ECG and belinostat plasma concentration data demonstrated no meaningful effect of Belinostat on cardiac repolarization. None of the trials showed any clinically relevant changes caused by Belinostat on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes. ## Pharmacokinetics - The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase 1/2 clinical studies that used doses of belinostat ranging from 150 to 1200 mg/m2. The total mean plasma clearance and elimination half-life were 1240 mL/min and 1.1 hours, respectively. The total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic extraction (clearance being flow dependent). - The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution. In vitro plasma studies have shown that between 92.9% and 95.8% of belinostat is bound to protein in an equilibrium dialysis assay, and was independent of belinostat plasma concentrations from 500 to 25,000 ng/mL. - Belinostat is primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known. - Belinostat is eliminated predominantly through metabolism with less than 2% of the dose recovered unchanged in urine. All major human metabolites (methyl belinostat, belinostat amide, belinostat acid, belinostat glucuronide, and 3-ASBA) are generally excreted in urine within the first 24 hours after dose administration. Metabolites 3-ASBA and belinostat glucuronide represented the highest fractions of the belinostat dose excreted in urine (4.61% and 30.5%, respectively). - In vitro studies showed belinostat and its metabolites (including belinostat glucuronide, belinostat amide, methyl belinostat) inhibited metabolic activities of CYP2C8 and CYP2C9. Other metabolites (3-ASBA and belinostat acid) inhibited CYP2C8. - In cancer patients, co-administration of Belinostat (1,000 mg/m2) and warfarin (5 mg), a known CYP2C9 substrate, did not increase the AUC or Cmax of either R- or S-warfarin. - Belinostat is likely a glycoprotein (P-gp) substrate but is unlikely to inhibit P-gp. - UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A128 polymorphism. Approximately 20% of the black population, 10% of the white population, and 2% of the Asian population are homozygous for the UGT1A128 allele. Additional reduced function alleles may be more prevalent in specific populations. - Because belinostat is primarily (80 -90%) metabolized by UGT1A1, the clearance of belinostat could be decreased in patients with reduced UGT1A1 activity (e.g., patients with UGT1A128 allele). Reduce the starting dose of Belinostat to 750 mg/m2 in patients known to be homozygous for the UGT1A1*28 allele to minimize dose limiting toxicities. ## Nonclinical Toxicology - Carcinogenicity studies have not been performed with belinostat. - Belinostat was genotoxic in a bacterial reverse mutation test (Ames assay), an in vitro mouse lymphoma cell mutagenesis assay, and an in vivo rat micronucleus assay. - Belinostat may impair male fertility. Fertility studies using belinostat were not conducted. However, belinostat effects on male reproductive organs observed during the 24-week repeat-dose dog toxicology study included reduced organ weights of the testes/epididymides that correlated with a delay in testicular maturation # Clinical Studies - In an open-label, single-arm, non-randomized international trial conducted at 62 centers, 129 patients with relapsed or refractory PTCL were treated with Belinostat 1,000 mg/m2 administered over 30 minutes via IV infusion once daily on Days 1-5 of a 21-day cycle. There were 120 patients who had histologically confirmed PTCL by central review evaluable for efficacy. Patients were treated with repeat cycles every three weeks until disease progression or unacceptable toxicity. - The primary efficacy endpoint was response rate (complete response and partial response) as assessed by an independent review committee (IRC) using the International Workshop Criteria (IWC) (Cheson 2007). The key secondary efficacy endpoint was duration of response. Response assessments were evaluated every 6 weeks for the first 12 months and then every 12 weeks until 2 years from the start of study treatment. Duration of response was measured from the first day of documented response to disease progression or death. Response and progression of disease were evaluated by the IRC using the IWC. - Table 3 summarizes the baseline demographic and disease characteristics of the study population, who were evaluable for efficacy. - The median duration of response based on the first date of response to disease progression or death was 8.4 months (95% CI: 4.5 – 29.4). Of the responders, the median time to response was 5.6 weeks (range 4.3 - 50.4 weeks). Nine patients (7.5%) were able to proceed to a stem cell transplant after treatment with Belinostat . # How Supplied - Belinostat (belinostat) for injection is supplied in single vial cartons; each 30 mL clear vial contains sterile, lyophilized powder equivalent to 500 mg belinostat. - NDC 68152-108-09: Individual carton of Belinostat 30 mL single-use vial containing 500 mg belinostat. ## Storage - Store Belinostat (belinostat) for injection at room temperature 20°C to 25°C (68°C to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). Retain in original package until use. . - Belinostat is a cytotoxic drug. Follow special handling and disposal procedures # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Physicians should discuss the FDA approved Patient Information Leaflet with patients prior to treatment with Belinostat . Instruct patients to read the Patient Information Leaflet carefully. - Advise the patient or the caregiver to read the FDA-approved patient labeling (Patient Information). - Advise patients or their caregivers: - To report symptoms of nausea, vomiting and diarrhea so that appropriate antiemetic and antidiarrheal medications can be administered - To report any symptoms of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia . - To immediately report symptoms of infection (e.g., pyrexia) . - Of the potential risk to the fetus and for women to avoid pregnancy while receiving Belinostat . - To understand the importance of monitoring liver function test abnormalities and to immediately report potential symptoms of liver injury # Precautions with Alcohol - Alcohol-Belinostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Belinostat ® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Belinostat
39385867ec3c766964cb4caaafb6ee190ab65046	wikidoc	Belzutifan	Belzutifan # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Belzutifan is a hypoxia-inducible factor inhibitor that is FDA approved for the treatment of von Hippel-Lindau disease under certain conditions. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, increased creatinine, nausea, anemia, decreased hemoglobin, dizziness, fatigue, and increased glucose. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - 120 mg is the recommended dosage of Belzutifan given to patients through oral administration once daily. - Recommended dosage is given until disease progression or unacceptable toxicity. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belzutifan in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belzutifan in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Belzutifan FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belzutifan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belzutifan in pediatric patients. # Contraindications There are no contraindications associated with Belzutifan. # Warnings Anemia - Severe anemia can occur when taking Belzutifan. - In Study 004, 90% of patients had experienced anemia in which 7% of these patients were experiencing Grade 3 Anemia when taking Belzutifan. - In Study 004, median time to onset of anemia was 31 days. - In Study 001, 76% of patients with advanced solid tumors displayed anemia. Of those patients with anemia, 28% displayed symptoms of Grade 3 anemia. - Advise patients to be on the alert for anemia when treated with Belzutifan. - Advise patients that severity of anemia can increase in patients who are dual CYP2C19 and UGT2B17 poor metabolizers. - Withhold Belzutifan treatment in patients with hemoglobin <9g/dL or are experiencing life threatening anemia. - Advise patients who's hemoglobin ≥9g/dL to either reduce their dosage or permanently stop Belzutifan use. - Advise patients treated with Belzutifan that erythropoiesis stimulating agents is not recommended for anemia treatment. - Advise patients that data from clinical studies show that the risk of serious cardiovascular reactions and death are increased when taking erythropoiesis stimulating agents. - Advise patients that data from clinical studies show that there is a decrease in progression-free survival and/or overall survival when taking erythropoiesis stimulating agents. Hypoxia - Hypoxia may be caused by patients treated with Belzutifan that may lead to discontinuation of treatment, supplemental oxygen, or hospitalization. - Study 004 showed that 1.6% of patients in the study that were treated with Belzutifan reported hypoxia. - In Study 001, 29% of patients with advanced solid tumors displayed hypoxia. Of those patients with hypoxia, 16% displayed symptoms of Grade 3 hypoxia. - Advise patients before start of, and throughout the treatment with Belzutifan to monitor oxygen saturation. - Withhold treatment of Belzutifan in patients with decreased oxygen saturation (pulse oximeter <88% or PaO2 ≤55 mm Hg) until issue is resolved. - Advise patients to permanently stop Belzutifan treatment if experiencing recurrent symptomatic hypoxia or life-threatening hypoxia. Embryo-Fetal Toxicity - Animal studies have shown that there is risk associated with the fetus in pregnant women who are taking Belzutifan. - Studies done on pregnant rats have shown that reduced fetal body weight, embryo-fetal lethality, and fetal skeletal malformations when given maternal exposures ≥0.2 times the human exposures of Belzutifan during the period of organogenesis. - Advise female patients with reproductive potential and pregnant women the risks associated to the fetus when treated with Belzutifan. - Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Belzutifan and for at least 1 week after the last dose. - Advise males with female partners of reproductive potential to use effective contraception during treatment with Belzutifan and for at least 1 week after the last dose. # Adverse Reactions ## Clinical Trials Experience Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Study 004, an open-label clinical trial, looked into the safety of Belzutifan in 61 patients with VHL disease who had at least one measurable solid tumor localized to the kidney. These patients received the recommended dosage of 120 mg of Belzutifan once daily for a median duration of 68 weeks. Study 004 - 15% of patients reported serious adverse reactions when treated with Belzutifan which included anaphylaxis reaction, central retinal vein occlusion, hypoxia, retinal detachment and anemia. Adverse reactions caused 3.3% of patients to permanently discontinue Belzutifan treatment. Of the 3.3% of patients who discontinued treatment, opioid overdose and dizziness were the most common adverse reactions that led to discontinuation. Adverse reactions caused 39% of taking Belzutifan to interrupt the dosage being taken. Headache, fatigue, influenza-like illness, decreased hemoglobin, nausea, anemia, and abdominal pain are some of the adverse reactions that caused dosage interruptions. Adverse reactions caused 13% of patients taking Belzutifan to reduce their dosage. Fatigue was the most common adverse reaction that caused a dosage reduction. - Fatigue, increased glucose, decreased hemoglobin, headache, nausea, dizziness, and increased creatinine are the most reported adverse reactions when patients are treated with Belzutifan. Table 2 summarizes the Adverse Reactions that occurred during Study 004 of Patients taking Belzutifan. Table 3 summarizes the Laboratory abnormalities in Study 004 in Patients taking Belzutifan. Other Clinical Trials Experience - Study 001 is a clinical trial that contained 58 patients with advanced solid tumors. These patients had a median age of 62.5 years and a median number of prior therapies for cancer was 3. These patients received the recommended dosage of Belzutifan once daily. The most common adverse reactions reported in this clinical trial was cough, dehydration, vomiting, edema, diarrhea, and musculoskeletal pain. ## Postmarketing Experience There is limited information regarding Belzutifan Postmarketing Experience in the drug label. # Drug Interactions Effects of Other Drugs on Belzutifan UGT2B17 or CYP2C19 Inhibitors - Plasma exposures of Belzutifan may increase with coadministration of UGT2B17 or CYP2C19 inhibitors and Belzutifan. - Adverse reactions of Belzutifan may increase when the plasma exposures of Belzutifan are elevated. - Reduce the dosage of Belzutifan if patients is experiencing hypoxia or anemia. Effect of WELIREG on Other Drugs Sensitive CYP3A4 Substrates - CYP3A substrates concentrations decreased with coadministration of CYP3A substrates and Belzutifan. - Patients with dual UGT2B17 and CYP2C19 poor metabolizers are more likely to experience a pronounced decrease in the *CYP3A substrates concentrations. - Advise patients to avoid coadministration of sensitive CYP3A4 substrates and Belzutifan. - Advise patients the dosage of sensitive CYP3A4 substrate should be increased if coadministration cannot be avoided. Hormonal Contraceptives - Increase in breakthrough bleeding or contraceptive failure may occur in patients with coadministration of hormonal contraceptives and Belzutifan. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Fetal harm may occur in pregnant women who are treated with Belzutifan based on data from animal studies. Pregnant rat studies have shown that there was evidence of reduced fetal body weight, embryo-fetal lethality, and fetal skeletal malformations during the period of organogenesis when given maternal exposures ≥0.2 times the human exposure. Embryo-fetal lethality was seen in pregnant rats that were given doses ≥60 mg/kg/day of Belzutifan during the period of organogenesis. Reduced skeletal ossification, reduced fetal body weights, and fetal rib malformations were seen in pregnant rats that were given doses of 6 and 60 mg/kg/day of Belzutifan. Advise pregnant women or females with reproductive potential about the harms associated with the fetus when treated with Belzutifan. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belzutifan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Belzutifan during labor and delivery. ### Nursing Mothers No data is present on the effects done on the breastfed child and the effects on milk production when treated with Belzutifan. Advise women who are nursing to not nurse during or 1 week after the last of dose of Belzutifan treatment due to the potential serious adverse reactions associated with Belzutifan. ### Pediatric Use There is no FDA guidance on the use of Belzutifan in pediatric settings. ### Geriatic Use There were not enough patients in clinical studies to look into the differences of Belzutifan in younger patients to patients who are 65 years of age or older. ### Gender There is no FDA guidance on the use of Belzutifan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Belzutifan with respect to specific racial populations. ### Renal Impairment Patients with mild or moderate renal impairment required no dose modifications in Belzutifan treatment. The effects of Belzutifan treatment on patients with severe renal impairment have not been established. ### Hepatic Impairment Patients with mild hepatic impairment required no dose modifications in Belzutifan treatment. The effects of Belzutifan treatment on patients with severe hepatic impairment have not been established. ### Females of Reproductive Potential and Males Advise patients that fetal harm may occur in pregnant women treated with Belzutifan. Verify the pregnancy status of the female patient before starting Belzutifan treatment. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Belzutifan and for at least 1 week after the last dose. Advise male patients with females of reproductive potential to use effective contraception during treatment with Belzutifan and for at least 1 week after the last dose. Fertility may be impaired in both male and female patients who are treated with Belzutifan. ### Immunocompromised Patients There is no FDA guidance one the use of Belzutifan in patients who are immunocompromised. ### Dual UGT2B17 and CYP2C19 Poor Metabolizers Higher Belzutifan exposures in patients with dual CYP2C19 and UGT2B17 poor metabolizers. Serious adverse reactions susceptibility may increase when exposures of Belzutifan are high. Monitor patients with dual CYP2C19 and UGT2B17 poor metabolizers that are treated with Belzutifan for adverse reactions. # Administration and Monitoring ### Administration - Advise patients to swallow tablets whole. - Prior to swallowing, advise patients to not crush, spit, or chew Belzutifan. - If a dosage of Belzutifan is missed, then it can be taken the same day as soon as possible. - Advise patients who missed a dose to not take extra tablets to make up for that dose which was missed. ### Monitoring Dose Reductions - 80 mg orally once daily of Belzutifan would be the first dose reduction. - 40 mg orally once daily of Belzutifan would be the second dose reduction. - Permanently discontinue Belzutifan if a third dose reduction is needed. Table 1 summarizes Dosage Modifications in Patients experiencing Adverse Reactions. # IV Compatibility There is limited information regarding the compatibility of Belzutifan and IV administrations. # Overdosage - No specific treatment is specified if a Belzutifan overdose occurs. - Advise patients to withhold institute supportive care and Belzutifan if a suspected overdose has occurred. - 120 mg twice a day of Belzutifan has resulted in Grade 3 hypoxia. - 240 mg once daily of Belzutifan has resulted in Grade 4 Thrombocytopenia. # Pharmacology ## Mechanism of Action - Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha. - Ubiquitin-proteasomal degradation by VHL protein targets HIF-2α when there are normal oxygen levels. - Accumulation and stabilization of HIF-2α when there is a lack of VHL protein. - A transcriptional complex is formed between HIF-2α and HIF-1β upon stabilization that induces expression of downstream genes associated with angiogenesis, cellular proliferation, and tumor growth. - HIF-2α-HIF-1β interaction is blocked when a patient is treated with Belzutifan. ## Structure - Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha. It has an empirical formula of C17H12F3NO4S and a molecular weight of 383.34 Daltons. ## Pharmacodynamics - When given up to 120mg of Belzutifan once daily, there were reductions in the plasma levels of EPO. - 2 weeks of Belzutifan led to maximum EPO suppression. - After 12 weeks of Belzutifan treatment, the levels of mean EPO returned to the values found at baseline. - Patients with baseline hemoglobin levels <12 g/dL were more likely to experience, when given higher doses of Belzutifan, Grade 3 Anemia. Cardiac Electrophysiology - Large mean increases in the QT interval is not caused by Belzutifan given at the recommended dosage in patients. ## Pharmacokinetics Mean steady-state - In patients with VHL disease-associated RCC, the Cmax of Belzutifan is 1.3 μg/mL. - In patients with VHL disease-associated RCC, the AUC0-24h of Belzutifan is 16.7 μghr/mL. - It takes about 3 days to reach steady state of Belzutifan. - Over a dose range of 20 mg to 120 mg of Belzutifan, the AUC and Cmax increase proportionally. Absorption - After 1 to 2 hours of Belzutifan administration, the Tmax median occurs. Effect of Food - Peak Belzutifan concentration was delayed by about 2 hours after a patient is given a high-fat, high-calorie meal. - There was no clinically meaningful effect on Cmax when patients were given a high-fat, high-calorie meal. - There was no effect done on AUC when patients were given a a high-fat, high-calorie meal. Distribution - 130 L is the mean steady-state volume of distribution for Belzutifan. - 45% is the plasma protein binding percentage of Belzutifan. - 0.88 is the Blood-to-plasma concentration ratio of Belzutifan. Elimination - 7.3 L/hr is the mean clearance of Belzutifan. - 14 hrs is the mean elimination half-life of Belzutifan. Metabolism - CYP2C19 and UGT2B17 primarily metabolizes Belzutifan. - CYP3A4 also shows signs of metabolizing Belzutifan. Specific Populations - A higher AUC of Belzutifan was detected in patients who are poor metabolizers of CYP2C19 and UGT2B17. - Mild to moderate renal impairment, sex, age, ethnicity, mild hepatic impairment, or body weight did not cause any clinically significant differences in the pharmacokinetics of patients who are treated with Belzutifan. - Differences in pharmacokinetics have not been studied in patients with moderate to severe hepatic impairment or severe renal impairment. Drug Interaction Studies Clinical Studies and Model-Informed Approaches: Effect of Belzutifan on CYP3A Substrates: - The AUC of Midazolam decreased by 40% when there is coadministration of Midazolam and 120 mg of Belzutifan once daily. - The Cmax of Midazolam decreased by 34% when there is coadministration of Midazolam and 120 mg of Belzutifan once daily. - Higher Belzutifan concentrations may cause a decrease of up to 70% in the AUC of Midazolam. In Vitro Studies: Cytochrome P450 (CYP) Enzymes: - CYP2B6, CYP2C8, CYP3A4, CYP2C19, CYP1A2, or CYP2D6 are not inhibited by Belzutifan. - CYP2B6 or CYP1A2 are not induced by Belzutifan. Transporter Systems: - Belzutifan is a substrate of OATP1B1, P-gp, and OATP1B3. - Belzutifan is not a substrate of BCRP. - MATE2K is inhibited by Belzutifan. - OATP1B1, OATP1B3, MATE1, P-gp, OCT2, OAT1, BCRP, and OAT3 are not inhibited by Belzutifan. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Studies on carcinogenicity have not been conducted on Belzutifan. - In vitro bacterial reverse mutation assay, Belzutifan was not mutagenic. - In vivo rat bone marrow micronucleus assay or in a vitro micronucleus assay, Belzutifan was not clastogenic. - Studies on animal fertility when given Belzutifan have not been conducted. - Rat studies show cellular debris and hypospermia of the epididymis when given ≥2 mg/kg/day of Belzutifan in a repeat-dose toxicity study that lasted 3 months. - Rat studies show degeneration/atrophy of testes when given ≥2 mg/kg/day of Belzutifan in a repeat-dose toxicity study that lasted 3 months. - There was abnormal sperm morphology, decreased sperm motility, and decreased sperm count in rats who were administered ≥6 mg/kg/day of Belzutifan that did not return to normal levels during the recovery period. - No adverse effects were seen on female reproductive organs of pregnant rats when given Belzutifan. - During the period of organogenesis, pregnant rats experienced embryo-fetal lethality when given oral doses that were ≥60 mg/kg/day of Belzutifan. # Clinical Studies Study 004 - A open-label clinical study was conducted on 61 patients with at least one measurable solid tumor localized to the kidney as defined by response evaluation criteria in solid tumors v1.1. These patients also had VHL-associated RCC diagnosed based on a VHL germline alteration. The patient population was largely Caucasian (90%), and included 53% males, and had a mean age of 41 years. 2.2 cm was the median diameter of RCC target lesions. 17.9 months is the median time from initial radiographic diagnosis of VHL-associated RCC tumors. Table 4 shows the Efficacy Results of Belzutifan in VHL-associated RCC Patients found in Study 004. Table 5 shows the Efficacy Results of Belzutifan in VHL-associated pNET or CNS Hemangioblastomas Patients found in Study 004. # How Supplied How Supplied - Belzutifan is given as blue tablets that are 40 mg. - Bottles contain 90 tablets that also contain child resistant seals. - Belzutifan bottles contains two desiccant canisters which should not be eaten. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Anemia - Advise patients that severe anemia may occur as a result of Belzutifan treatment. - Advise patients that severe anemia may require blood transfusions. - Monitor patients red blood cell levels during Belzutifan treatment. - Advise patients to seek medical attention if they display signs of severe anemia. Hypoxia - Advise patients that severe hypoxia may occur when treated with Belzutifan. - Advise patients that severe hypoxia may require supplemental oxygen, discontinuation of treatment, or hospitalization. - Monitor patients oxygen levels during Belzutifan treatment. - Advise patients to seek medical attention if they display signs of severe hypoxia. Embryo-Fetal Toxicity - Advise pregnant patients and females of reproductive potential to consider the risks associated to the fetus when treated with Belzutifan. - Advise female patients that suspect they may be pregnant to inform their doctor. - Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Belzutifan and for at least 1 week after the last dose. - Advise male patients with females of reproductive potential to use effective contraception during treatment with Belzutifan and for at least 1 week after the last dose. Lactation - Advise women who are nursing to not nurse during or 1 week after the last of dose of Belzutifan treatment. Infertility - Advise both male and female patients that fertility may be impaired when taking Belzutifan. Dosage and Administration - Advise patients to take Belzutifan once daily at the same time each day. - Advise patients that Belzutifan may be take with or without food. - Advise patients to swallow Belzutifan tablets whole. Belzutifan Package Insert: # Precautions with Alcohol Alcohol-Belzutifan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Welireg # Look-Alike Drug Names There is limited information regarding Belzutifan Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Belzutifan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Belzutifan is a hypoxia-inducible factor inhibitor that is FDA approved for the treatment of von Hippel-Lindau disease under certain conditions. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, increased creatinine, nausea, anemia, decreased hemoglobin, dizziness, fatigue, and increased glucose. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - 120 mg is the recommended dosage of Belzutifan given to patients through oral administration once daily. - Recommended dosage is given until disease progression or unacceptable toxicity. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belzutifan in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belzutifan in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Belzutifan FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Belzutifan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Belzutifan in pediatric patients. # Contraindications There are no contraindications associated with Belzutifan. # Warnings Anemia - Severe anemia can occur when taking Belzutifan. - In Study 004, 90% of patients had experienced anemia in which 7% of these patients were experiencing Grade 3 Anemia when taking Belzutifan. - In Study 004, median time to onset of anemia was 31 days. - In Study 001, 76% of patients with advanced solid tumors displayed anemia. Of those patients with anemia, 28% displayed symptoms of Grade 3 anemia. - Advise patients to be on the alert for anemia when treated with Belzutifan. - Advise patients that severity of anemia can increase in patients who are dual CYP2C19 and UGT2B17 poor metabolizers. - Withhold Belzutifan treatment in patients with hemoglobin <9g/dL or are experiencing life threatening anemia. - Advise patients who's hemoglobin ≥9g/dL to either reduce their dosage or permanently stop Belzutifan use. - Advise patients treated with Belzutifan that erythropoiesis stimulating agents is not recommended for anemia treatment. - Advise patients that data from clinical studies show that the risk of serious cardiovascular reactions and death are increased when taking erythropoiesis stimulating agents. - Advise patients that data from clinical studies show that there is a decrease in progression-free survival and/or overall survival when taking erythropoiesis stimulating agents. Hypoxia - Hypoxia may be caused by patients treated with Belzutifan that may lead to discontinuation of treatment, supplemental oxygen, or hospitalization. - Study 004 showed that 1.6% of patients in the study that were treated with Belzutifan reported hypoxia. - In Study 001, 29% of patients with advanced solid tumors displayed hypoxia. Of those patients with hypoxia, 16% displayed symptoms of Grade 3 hypoxia. - Advise patients before start of, and throughout the treatment with Belzutifan to monitor oxygen saturation. - Withhold treatment of Belzutifan in patients with decreased oxygen saturation (pulse oximeter <88% or PaO2 ≤55 mm Hg) until issue is resolved. - Advise patients to permanently stop Belzutifan treatment if experiencing recurrent symptomatic hypoxia or life-threatening hypoxia. Embryo-Fetal Toxicity - Animal studies have shown that there is risk associated with the fetus in pregnant women who are taking Belzutifan. - Studies done on pregnant rats have shown that reduced fetal body weight, embryo-fetal lethality, and fetal skeletal malformations when given maternal exposures ≥0.2 times the human exposures of Belzutifan during the period of organogenesis. - Advise female patients with reproductive potential and pregnant women the risks associated to the fetus when treated with Belzutifan. - Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Belzutifan and for at least 1 week after the last dose. - Advise males with female partners of reproductive potential to use effective contraception during treatment with Belzutifan and for at least 1 week after the last dose. # Adverse Reactions ## Clinical Trials Experience Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Study 004, an open-label clinical trial, looked into the safety of Belzutifan in 61 patients with VHL disease who had at least one measurable solid tumor localized to the kidney. These patients received the recommended dosage of 120 mg of Belzutifan once daily for a median duration of 68 weeks. Study 004 - 15% of patients reported serious adverse reactions when treated with Belzutifan which included anaphylaxis reaction, central retinal vein occlusion, hypoxia, retinal detachment and anemia. Adverse reactions caused 3.3% of patients to permanently discontinue Belzutifan treatment. Of the 3.3% of patients who discontinued treatment, opioid overdose and dizziness were the most common adverse reactions that led to discontinuation. Adverse reactions caused 39% of taking Belzutifan to interrupt the dosage being taken. Headache, fatigue, influenza-like illness, decreased hemoglobin, nausea, anemia, and abdominal pain are some of the adverse reactions that caused dosage interruptions. Adverse reactions caused 13% of patients taking Belzutifan to reduce their dosage. Fatigue was the most common adverse reaction that caused a dosage reduction. - Fatigue, increased glucose, decreased hemoglobin, headache, nausea, dizziness, and increased creatinine are the most reported adverse reactions when patients are treated with Belzutifan. Table 2 summarizes the Adverse Reactions that occurred during Study 004 of Patients taking Belzutifan. Table 3 summarizes the Laboratory abnormalities in Study 004 in Patients taking Belzutifan. Other Clinical Trials Experience - Study 001 is a clinical trial that contained 58 patients with advanced solid tumors. These patients had a median age of 62.5 years and a median number of prior therapies for cancer was 3. These patients received the recommended dosage of Belzutifan once daily. The most common adverse reactions reported in this clinical trial was cough, dehydration, vomiting, edema, diarrhea, and musculoskeletal pain. ## Postmarketing Experience There is limited information regarding Belzutifan Postmarketing Experience in the drug label. # Drug Interactions Effects of Other Drugs on Belzutifan UGT2B17 or CYP2C19 Inhibitors - Plasma exposures of Belzutifan may increase with coadministration of UGT2B17 or CYP2C19 inhibitors and Belzutifan. - Adverse reactions of Belzutifan may increase when the plasma exposures of Belzutifan are elevated. - Reduce the dosage of Belzutifan if patients is experiencing hypoxia or anemia. Effect of WELIREG on Other Drugs Sensitive CYP3A4 Substrates - CYP3A substrates concentrations decreased with coadministration of CYP3A substrates and Belzutifan. - Patients with dual UGT2B17 and CYP2C19 poor metabolizers are more likely to experience a pronounced decrease in the *CYP3A substrates concentrations. - Advise patients to avoid coadministration of sensitive CYP3A4 substrates and Belzutifan. - Advise patients the dosage of sensitive CYP3A4 substrate should be increased if coadministration cannot be avoided. Hormonal Contraceptives - Increase in breakthrough bleeding or contraceptive failure may occur in patients with coadministration of hormonal contraceptives and Belzutifan. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Fetal harm may occur in pregnant women who are treated with Belzutifan based on data from animal studies. Pregnant rat studies have shown that there was evidence of reduced fetal body weight, embryo-fetal lethality, and fetal skeletal malformations during the period of organogenesis when given maternal exposures ≥0.2 times the human exposure. Embryo-fetal lethality was seen in pregnant rats that were given doses ≥60 mg/kg/day of Belzutifan during the period of organogenesis. Reduced skeletal ossification, reduced fetal body weights, and fetal rib malformations were seen in pregnant rats that were given doses of 6 and 60 mg/kg/day of Belzutifan. Advise pregnant women or females with reproductive potential about the harms associated with the fetus when treated with Belzutifan. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belzutifan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Belzutifan during labor and delivery. ### Nursing Mothers No data is present on the effects done on the breastfed child and the effects on milk production when treated with Belzutifan. Advise women who are nursing to not nurse during or 1 week after the last of dose of Belzutifan treatment due to the potential serious adverse reactions associated with Belzutifan. ### Pediatric Use There is no FDA guidance on the use of Belzutifan in pediatric settings. ### Geriatic Use There were not enough patients in clinical studies to look into the differences of Belzutifan in younger patients to patients who are 65 years of age or older. ### Gender There is no FDA guidance on the use of Belzutifan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Belzutifan with respect to specific racial populations. ### Renal Impairment Patients with mild or moderate renal impairment required no dose modifications in Belzutifan treatment. The effects of Belzutifan treatment on patients with severe renal impairment have not been established. ### Hepatic Impairment Patients with mild hepatic impairment required no dose modifications in Belzutifan treatment. The effects of Belzutifan treatment on patients with severe hepatic impairment have not been established. ### Females of Reproductive Potential and Males Advise patients that fetal harm may occur in pregnant women treated with Belzutifan. Verify the pregnancy status of the female patient before starting Belzutifan treatment. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Belzutifan and for at least 1 week after the last dose. Advise male patients with females of reproductive potential to use effective contraception during treatment with Belzutifan and for at least 1 week after the last dose. Fertility may be impaired in both male and female patients who are treated with Belzutifan. ### Immunocompromised Patients There is no FDA guidance one the use of Belzutifan in patients who are immunocompromised. ### Dual UGT2B17 and CYP2C19 Poor Metabolizers Higher Belzutifan exposures in patients with dual CYP2C19 and UGT2B17 poor metabolizers. Serious adverse reactions susceptibility may increase when exposures of Belzutifan are high. Monitor patients with dual CYP2C19 and UGT2B17 poor metabolizers that are treated with Belzutifan for adverse reactions. # Administration and Monitoring ### Administration - Advise patients to swallow tablets whole. - Prior to swallowing, advise patients to not crush, spit, or chew Belzutifan. - If a dosage of Belzutifan is missed, then it can be taken the same day as soon as possible. - Advise patients who missed a dose to not take extra tablets to make up for that dose which was missed. ### Monitoring Dose Reductions - 80 mg orally once daily of Belzutifan would be the first dose reduction. - 40 mg orally once daily of Belzutifan would be the second dose reduction. - Permanently discontinue Belzutifan if a third dose reduction is needed. Table 1 summarizes Dosage Modifications in Patients experiencing Adverse Reactions. # IV Compatibility There is limited information regarding the compatibility of Belzutifan and IV administrations. # Overdosage - No specific treatment is specified if a Belzutifan overdose occurs. - Advise patients to withhold institute supportive care and Belzutifan if a suspected overdose has occurred. - 120 mg twice a day of Belzutifan has resulted in Grade 3 hypoxia. - 240 mg once daily of Belzutifan has resulted in Grade 4 Thrombocytopenia. # Pharmacology ## Mechanism of Action - Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha. - Ubiquitin-proteasomal degradation by VHL protein targets HIF-2α when there are normal oxygen levels. - Accumulation and stabilization of HIF-2α when there is a lack of VHL protein. - A transcriptional complex is formed between HIF-2α and HIF-1β upon stabilization that induces expression of downstream genes associated with angiogenesis, cellular proliferation, and tumor growth. - HIF-2α-HIF-1β interaction is blocked when a patient is treated with Belzutifan. ## Structure - Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha. It has an empirical formula of C17H12F3NO4S and a molecular weight of 383.34 Daltons. ## Pharmacodynamics - When given up to 120mg of Belzutifan once daily, there were reductions in the plasma levels of EPO. - 2 weeks of Belzutifan led to maximum EPO suppression. - After 12 weeks of Belzutifan treatment, the levels of mean EPO returned to the values found at baseline. - Patients with baseline hemoglobin levels <12 g/dL were more likely to experience, when given higher doses of Belzutifan, Grade 3 Anemia. Cardiac Electrophysiology - Large mean increases in the QT interval is not caused by Belzutifan given at the recommended dosage in patients. ## Pharmacokinetics Mean steady-state - In patients with VHL disease-associated RCC, the Cmax of Belzutifan is 1.3 μg/mL. - In patients with VHL disease-associated RCC, the AUC0-24h of Belzutifan is 16.7 μg•hr/mL. - It takes about 3 days to reach steady state of Belzutifan. - Over a dose range of 20 mg to 120 mg of Belzutifan, the AUC and Cmax increase proportionally. Absorption - After 1 to 2 hours of Belzutifan administration, the Tmax median occurs. Effect of Food - Peak Belzutifan concentration was delayed by about 2 hours after a patient is given a high-fat, high-calorie meal. - There was no clinically meaningful effect on Cmax when patients were given a high-fat, high-calorie meal. - There was no effect done on AUC when patients were given a a high-fat, high-calorie meal. Distribution - 130 L is the mean steady-state volume of distribution for Belzutifan. - 45% is the plasma protein binding percentage of Belzutifan. - 0.88 is the Blood-to-plasma concentration ratio of Belzutifan. Elimination - 7.3 L/hr is the mean clearance of Belzutifan. - 14 hrs is the mean elimination half-life of Belzutifan. Metabolism - CYP2C19 and UGT2B17 primarily metabolizes Belzutifan. - CYP3A4 also shows signs of metabolizing Belzutifan. Specific Populations - A higher AUC of Belzutifan was detected in patients who are poor metabolizers of CYP2C19 and UGT2B17. - Mild to moderate renal impairment, sex, age, ethnicity, mild hepatic impairment, or body weight did not cause any clinically significant differences in the pharmacokinetics of patients who are treated with Belzutifan. - Differences in pharmacokinetics have not been studied in patients with moderate to severe hepatic impairment or severe renal impairment. Drug Interaction Studies Clinical Studies and Model-Informed Approaches: Effect of Belzutifan on CYP3A Substrates: - The AUC of Midazolam decreased by 40% when there is coadministration of Midazolam and 120 mg of Belzutifan once daily. - The Cmax of Midazolam decreased by 34% when there is coadministration of Midazolam and 120 mg of Belzutifan once daily. - Higher Belzutifan concentrations may cause a decrease of up to 70% in the AUC of Midazolam. In Vitro Studies: Cytochrome P450 (CYP) Enzymes: - CYP2B6, CYP2C8, CYP3A4, CYP2C19, CYP1A2, or CYP2D6 are not inhibited by Belzutifan. - CYP2B6 or CYP1A2 are not induced by Belzutifan. Transporter Systems: - Belzutifan is a substrate of OATP1B1, P-gp, and OATP1B3. - Belzutifan is not a substrate of BCRP. - MATE2K is inhibited by Belzutifan. - OATP1B1, OATP1B3, MATE1, P-gp, OCT2, OAT1, BCRP, and OAT3 are not inhibited by Belzutifan. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Studies on carcinogenicity have not been conducted on Belzutifan. - In vitro bacterial reverse mutation assay, Belzutifan was not mutagenic. - In vivo rat bone marrow micronucleus assay or in a vitro micronucleus assay, Belzutifan was not clastogenic. - Studies on animal fertility when given Belzutifan have not been conducted. - Rat studies show cellular debris and hypospermia of the epididymis when given ≥2 mg/kg/day of Belzutifan in a repeat-dose toxicity study that lasted 3 months. - Rat studies show degeneration/atrophy of testes when given ≥2 mg/kg/day of Belzutifan in a repeat-dose toxicity study that lasted 3 months. - There was abnormal sperm morphology, decreased sperm motility, and decreased sperm count in rats who were administered ≥6 mg/kg/day of Belzutifan that did not return to normal levels during the recovery period. - No adverse effects were seen on female reproductive organs of pregnant rats when given Belzutifan. - During the period of organogenesis, pregnant rats experienced embryo-fetal lethality when given oral doses that were ≥60 mg/kg/day of Belzutifan. # Clinical Studies Study 004 - A open-label clinical study was conducted on 61 patients with at least one measurable solid tumor localized to the kidney as defined by response evaluation criteria in solid tumors v1.1. These patients also had VHL-associated RCC diagnosed based on a VHL germline alteration. The patient population was largely Caucasian (90%), and included 53% males, and had a mean age of 41 years. 2.2 cm was the median diameter of RCC target lesions. 17.9 months is the median time from initial radiographic diagnosis of VHL-associated RCC tumors. Table 4 shows the Efficacy Results of Belzutifan in VHL-associated RCC Patients found in Study 004. Table 5 shows the Efficacy Results of Belzutifan in VHL-associated pNET or CNS Hemangioblastomas Patients found in Study 004. # How Supplied How Supplied - Belzutifan is given as blue tablets that are 40 mg. - Bottles contain 90 tablets that also contain child resistant seals. - Belzutifan bottles contains two desiccant canisters which should not be eaten. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Anemia - Advise patients that severe anemia may occur as a result of Belzutifan treatment. - Advise patients that severe anemia may require blood transfusions. - Monitor patients red blood cell levels during Belzutifan treatment. - Advise patients to seek medical attention if they display signs of severe anemia. Hypoxia - Advise patients that severe hypoxia may occur when treated with Belzutifan. - Advise patients that severe hypoxia may require supplemental oxygen, discontinuation of treatment, or hospitalization. - Monitor patients oxygen levels during Belzutifan treatment. - Advise patients to seek medical attention if they display signs of severe hypoxia. Embryo-Fetal Toxicity - Advise pregnant patients and females of reproductive potential to consider the risks associated to the fetus when treated with Belzutifan. - Advise female patients that suspect they may be pregnant to inform their doctor. - Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Belzutifan and for at least 1 week after the last dose. - Advise male patients with females of reproductive potential to use effective contraception during treatment with Belzutifan and for at least 1 week after the last dose. Lactation - Advise women who are nursing to not nurse during or 1 week after the last of dose of Belzutifan treatment. Infertility - Advise both male and female patients that fertility may be impaired when taking Belzutifan. Dosage and Administration - Advise patients to take Belzutifan once daily at the same time each day. - Advise patients that Belzutifan may be take with or without food. - Advise patients to swallow Belzutifan tablets whole. Belzutifan Package Insert: # Precautions with Alcohol Alcohol-Belzutifan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Welireg # Look-Alike Drug Names There is limited information regarding Belzutifan Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Belzutifan
bb0b45fc11046d19546a793bd15604e0ad503b18	wikidoc	Ben Humble	Ben Humble # Overview Benjamin Hutchison Humble M.B.E. lived in Arrochar from 1960 to 1970. He was a prolific author and a noted Scottish climber who was responsible for the creation of Scottish Mountain Rescue teams as we know them today. He was also a keen photographer and film maker. Ben Humble was born in Dumbarton in 1903, one of the sons of the manager of Dennystown Forge. Despite his total deafness he became a dentist, later making advances in forensic dentistry. His deafness made Bennie, as he was known, slightly crusty with people. A published, unflattering photograph called the Humble Kipper, showing him at breakfast, caused him not to speak to the photographer for 10 years. For further details please see the definitive web biography of Ben Humble on the Arrochar, Tarbet and Ardlui Heritage Group web site :- He died in 1977.	Ben Humble # Overview Benjamin Hutchison Humble M.B.E. lived in Arrochar from 1960 to 1970. He was a prolific author and a noted Scottish climber who was responsible for the creation of Scottish Mountain Rescue teams as we know them today. He was also a keen photographer and film maker. Ben Humble was born in Dumbarton in 1903, one of the sons of the manager of Dennystown Forge. Despite his total deafness he became a dentist, later making advances in forensic dentistry. His deafness made Bennie, as he was known, slightly crusty with people. A published, unflattering photograph called the Humble Kipper, showing him at breakfast, caused him not to speak to the photographer for 10 years. For further details please see the definitive web biography of Ben Humble on the Arrochar, Tarbet and Ardlui Heritage Group web site :- http://www.arrocharheritage.com/BenHumbleMBE.htm He died in 1977. Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Ben_Humble
dca23d60108695233df5bd50fbb551946216d711	wikidoc	Benazepril	Benazepril Synonyms / Brand Names: Lotensin® # Disclaimer WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer here. # Black Box Warning # Overview Benazepril is an angiotensin converting enzyme inhibitor drug that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cough, dizziness, fatigue, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial dose (not receiving a diuretic): Benazepril 10 mg PO qd - Initial dose (concurrent diuretic use): the diuretic should be discontinued 2 to 3 days prior to initiating Benazepril to reduce the likelihood of hypotension. If blood pressure is not controlled with Benazepril alone, diuretic should be resumed and Benazepril 5 mg PO qd should be used. - Maintenance dose:Benazepril 20—40 mg PO qd or Benazepril 10—20 mg PO bid (MAX 80 mg/day) - The divided regimen was more effective in controlling trough (pre-dosing) blood pressure than the same dose given as a once-daily regimen. Dosage adjustment should be based on measurement of peak (2-6 hours after dosing) and trough responses. If a once-daily regimen does not give adequate trough response, an increase in dosage or divided administration should be considered. - If blood pressure is not controlled with Benazepril alone, a diuretic can be added. - Concomitant administration of Benazepril with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium. - Dosing Information - Initial dose (for creatinine clearance 3 mg/dL):Benazepril 5 mg PO qd - Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg gs. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Cardiology (ACC) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level A - Recommendation - In all patients with a recent or remote history of MI or ACS and reduced EF, ACE inhibitors should be used to prevent symptomatic HF and reduce mortality. - Developed by: American College of Cardiology (ACC) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level A - Recommendation - An angiotensin-converting enzyme (ACE) inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction (EF) less than or equal to 0.40, unless contraindicated. ### Non–Guideline-Supported Use - Dosing Information - Benazepril 10 mg PO qd - Dosing Information - Benazepril 10 mg PO qd - Dosing Information - Benazepril 20 mg PO qd for 2 weeks, followed by Benazepril 40 mg qd or combination of Benazepril 40 mg PO qd and amlodipine 5 mg PO qd # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Initial dose: Benazepril 0.2 mg/kg PO qd (for pediatric patients above the age of 6 years) - Benazepril is not advised for children below the age of 6 years and in pediatric patients with glomerular filtration rate <30 mL. - For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths for Benazepril, follow the suspension preparation instructions to administer Benazepril HCl as a suspension. - Dosing Information - Initial dose (for creatinine clearance 3 mg/dL): Benazepril 5 mg PO qd - Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg. ## Off-Label Use and Dosage (Pediatric) There is limited information about Off-Label Use and Dosage of Benazepril tablet in pediatric patients. # Contraindications - Hypersensitivity to Benazepril or to any other ACE inhibitor - History of angioedema with or without previous ACE inhibitor treatment # Warnings - Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Benazepril) may be subject to a variety of adverse reactions, some of them serious. - Head and Neck Angioedema - Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received Benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Benazepril should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptly administered. - Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks. - Intestinal Angioedema - Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. - Anaphylactoid Reactions During Desensitization - Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. - Anaphylactoid Reactions During Membrane Exposure - Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States). - Benazepril can cause symptomatic hypotension. Like other ACE inhibitors, Benazepril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume-and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume-and/or salt-depletion should be corrected before initiating therapy with Benazepril. - In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, Benazepril therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of benazepril or diuretic is increased. - If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Benazepril treatment usually can be continued following restoration of blood pressure and volume. - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benazepril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benazepril, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Benazepril for hypotension, oliguria, and hyperkalemia. - No teratogenic effects of Benazepril were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose. - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. # Adverse Reactions ## Clinical Trials Experience - Benazepril has been evaluated for safety in over 6000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was comparable in Benazepril and placebo patients. - The reported side effects were generally mild and transient, and there was no relation between side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg. Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with Benazepril and in 3% of patients treated with placebo. - The most common reasons for discontinuation were headache (0.6%) and cough (0.5%) - The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril are shown below. - Other adverse experiences reported in controlled clinical trials (in less than 1% of Benazepril patients or with less than 1% difference in incidence between Benazepril or placebo treatment), and rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug use is uncertain): - Dermatologic - Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing. - Gastrointestinal - Nausea, pancreatitis, constipation, gastritis, vomiting, and melena. - Hematologic - Thrombocytopenia and hemolytic anemia. - Neurologic and Psychiatric - Anxiety, decreased libido, hypertonia, insomnia, nervousness, and paresthesia. - Other - Fatigue, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination, infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating. - Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors. - Clinical Laboratory Test Findings - Hemoglobin - Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were rare, occurring in only 1 of 2,014 patients receiving Benazepril alone and in 1 of 1,357 patients receiving Benazepril plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin. - Other (causal relationships unknown) - Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes have been reported, as have scattered incidents of hyponatremia, electrocardiographic changes, eosinophilia, and proteinuria. - Pediatric Patients - The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients. ## Postmarketing Experience - FDA Package Insert for Benazepril contains no information regarding Postmarketing Experience. # Drug Interactions Diuretics - Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril. The possibility of hypotensive effects with Benazepril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Benazepril. If this is not possible, the starting dose should be reduced. Potassium supplements and potassium-sparing diuretics - Concomitant use with Benazepril may effect potassium levels. Monitor potassium periodically. Oral anticoagulants - Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants. Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including Benazepril) during therapy with lithium. Monitor lithium levels when used concomitantly with Benazepril. Gold - Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Anti-diabetics - In rare cases, diabetic patients receiving an ACE inhibitor (including Benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly. NSAID\|Non-steroidal anti-inflammatory drugs (NSAIDs) including selective COX-2 inhibitor\|cyclooxygenase-2 inhibitors (COX-2 inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including Benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Benazepril and NSAID therapy. - The antihypertensive effect of ACE inhibitors, including Benazepril, may be attenuated by NSAIDs. Miscellaneous - Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important adverse interactions. Benazepril, like other ACE inhibitors, has had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system. - The pharmacokinetics of Benazepril are not affected by the following drugs: hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of Benazepril does not substantially affect the pharmacokinetics of these medications (cimetidine kinetics were not studied). # Use in Specific Populations ### Pregnancy - Fetal toxicity - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benazepril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benazepril, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Benazepril for hypotension, oliguria, and hyperkalemia. - No teratogenic effects of Benazepril were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose. ### Labor and Delivery - FDA Package Insert for Benazepril contains no information regarding Labor and Delivery. ### Nursing Mothers - Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril. A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of Benazepril and benazeprilat. ### Pediatric Use - Neonates with a history of in utero exposure to Benazepril - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited. - The antihypertensive effects of Benazepril have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age . The pharmacokinetics of Benazepril have been evaluated in pediatric patients 6 to 16 years of age . Benazepril was generally well tolerated and adverse effects were similar to those described in adults.The long-term effects of Benazepril on growth and development have not been studied. Infants below the age of 1 year should not be given Benazepril because of the risk of effects on kidney development. - Treatment with Benazepril is not recommended in pediatric patients less than 6 years of age , and in children with glomerular filtration rate <30 mL/min as there are insufficient data available to support a dosing recommendation in these groups. ### Geriatric Use - Of the total number of patients who received Benazepril in U.S. clinical studies of Benazepril, 18% were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender FDA Package Insert for Benazepril contains no information regarding Gender. ### Race FDA Package Insert for Benazepril contains no information regarding Race. ### Renal Impairment - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including Benazepril, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In a small study of hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, treatment with Benazepril was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of Benazepril or diuretic therapy, or both. When such patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Benazepril has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of Benazepril and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function. ### Hepatic Impairment - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. ### Carcinogenesis, Mutagenesis, Impairment of Fertility - No evidence of carcinogenicity was found when Benazepril was administered to rats and mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body weights, this dose is 110 times the maximum recommended human dose. When compared on the basis of body surface areas, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg). - No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. - In doses of 50-500 mg/kg/day (6-60 times the maximum recommended human dose based on mg/m2 comparison and 37-375 times the maximum recommended human dose based on a mg/kg comparison), Benazepril had no adverse effect on the reproductive performance of male and female rats. ### Immunocompromised Patients FDA Package Insert for Benazepril contains no information regarding Immunocompromised Patients. ### Miscellaneous Hyperkalemia - In clinical trials, hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal) occurred in approximately 1% of hypertensive patients receiving Benazepril. In most cases, these were isolated values which resolved despite continued therapy. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Benazepril. Cough - Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia - In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. # Administration and Monitoring ### Administration - Oral - Preparation of suspension (for 150 mL of a 2 mg/mL suspension) - Add 75 mL of Ora-Plus® oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen Benazepril 20 mg tablets, and shake for at least 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 75 mL of Ora-Sweet® oral syrup vehicle to the bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap closure. Shake the suspension before each use. ### Monitoring Geriatric Use - Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Overdose - Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure. Renal Artery Stenosis - When hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy. Use of Potassium Supplements and Potassium-Sparing Diuretics - Concomitant potassium supplements and potassium-sparing diuretics use with Benazepril may effect potassium levels. Monitor potassium periodically. Use of Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including Benazepril) during therapy with lithium. Monitor lithium levels when used concomitantly with Benazepril. Use of Anti-Diabetics - In rare cases, diabetic patients receiving an ACE inhibitor (including Benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly. Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Benazepril and NSAID therapy. # IV Compatibility FDA Package Insert for Benazepril contains no information regarding IV Compatibility. # Overdosage ## Acute Overdose ### Signs and Symptoms - Human overdoses of Benazepril have not been reported, but the most common manifestation of human Benazepril overdosage is likely to be hypotension, which can be associated with electrolyte disturbances and renal failure. ### Management - Laboratory determinations of serum levels of Benazepril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Benazepril overdose. - No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Benazepril and its metabolites. Benazepril is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see Warnings). - Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of Benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of Benazepril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Benazepril overdose by infusion of normal saline solution. - If ingestion is recent, activated charcoal should be considered. Gastric decontamination (e.g., vomiting, gastric lavage) may be considered in individual cases, in the early period after ingestion. - Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure. - In the case of marked hypotension, physiological saline solution should be administered intravenously; depending on the clinical situation the use of vasopressors (e.g., catecholamines i.v.) may be considered. ## Chronic Overdose ### Signs and Symptoms - FDA Package Insert for Benazepril contains no information regarding Signs and Symptoms in Chronic Overdose. ### Management - FDA Package Insert for Benazepril contains no information regarding Management in Chronic Overdose. # Pharmacology ## Mechanism of Action - Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. - Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with Benazepril alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with Benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium. - Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine. - ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Benazepril remains to be elucidated. - While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension. ## Structure - Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol. Its chemical name is benazepril 3-amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride. - Its empirical formula is C24H28N2O5HCl, and its molecular weight is 460.96. - Benazeprilat, the active metabolite of Benazepril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group. - Benazepril is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of benazepril hydrochloride for oral administration. The inactive ingredients are colloidal silicon dioxide, crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80, propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide. ## Pharmacodynamics - Single and multiple doses of 10 mg or more of Benazepril cause inhibition of plasma ACE activity by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg dose. ## Pharmacokinetics - Following oral administration of Benazepril, peak plasma concentrations of Benazepril are reached within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract. - Cleavage of the ester group (primarily in the liver) converts Benazepril to its active metabolite, benazeprilat. Peak plasma concentrations of benazeprilat are reached 1-2 hours after drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein binding of Benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-23.6 µmol/L). - Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE inhibitory activity than Benazepril, and to the glucuronide conjugates of Benazepril and benazeprilat. Only trace amounts of an administered dose of Benazepril can be recovered in the urine as unchanged Benazepril, while about 20% of the dose is excreted as benazeprilat, 4% as benazepril glucuronide, and 8% as benazeprilat glucuronide. - The kinetics of Benazepril are approximately dose-proportional within the dosage range of 10-80 mg. - In adults, the effective half-life of accumulation of benazeprilat following multiple dosing of benazepril hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily. - The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively. - Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance. - In patients with renal insufficiency, the disposition of benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance <30 mL/min, peak benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady state may be delayed (see Adult Indications and Dosage). - When dialysis was started 2 hours after ingestion of 10 mg of Benazepril, approximately 6% of benazeprilat was removed in 4 hours of dialysis. The parent compound, Benazepril, was not detected in the dialysate. - In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat are essentially unaltered. The pharmacokinetics of Benazepril and benazeprilat do not appear to be influenced by age. - In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of Benazepril (0.1 to 0.5 mg/kg), the clearance of benazeprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of benazeprilat in pediatric patients was around 5 hours, one-third that observed in adults. ## Nonclinical Toxicology - FDA Package Insert for Benazepril contains no information regarding Nonclinical Toxicology. # Clinical Studies - In single-dose studies, Benazepril lowered blood pressure within 1 hour, with peak reductions achieved 2-4 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 6-12/4-7 mmHg. The trough values represent reductions of about 50% of that seen at peak. - Four dose-response studies using once-daily dosing were conducted in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective once-daily dose of Benazepril was 10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10-80 mg). In studies comparing the same daily dose of Benazepril given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen. - The antihypertensive effects of Benazepril were not appreciably different in patients receiving high- or low-sodium diets. - In normal human volunteers, single doses of Benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate. - Use of Benazepril in combination with thiazide diuretics gives a blood-pressure-lowering effect greater than that seen with either agent alone. By blocking the renin-angiotensin-aldosterone axis, administration of Benazepril tends to reduce the potassium loss associated with the diuretic. - In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or 0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or Benazepril and were followed up for an additional two weeks. At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg more than in children on Benazepril. No dose-response was observed for the three doses. # How Supplied - Benazepril is available in tablets of 5 mg, 10 mg, 20 mg, and 40 mg, packaged with a desiccant in bottles of 100 tablets. - Each tablet is imprinted with Benazepril on one side and the tablet strength (“5,” “10,” “20,” or “40”) on the other. - National Drug Code (NDC): - Storage - Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP). - Manufactured by - Novartis Pharmaceuticals Corporation, Suffern, New York 10901 - Distributed by - Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 # Images ## Drug Images ## Package and Label Display Panel # Patient Information ## Patient Information from FDA - Pregnancy - Female patients of childbearing age should be told about the consequences of exposure to Benazepril during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. - Angioedema - Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician. - Symptomatic Hypotension - Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to the prescribing physician. Patients should be told that if syncope occurs, Benazepril should be discontinued until the prescribing physician has been consulted. - All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. - Hyperkalemia - Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. - Neutropenia - Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia. ## Patient Information from NLM For patient information about benazepril from NLM, click here. # Precautions with Alcohol Alcohol-Benazepril interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Lotensin® # Look-Alike Drug Names Benazepril — Benadryl® Lotensin® — Latensin®, Lioresal®, Lovastatin # Drug Shortage Status # Price	Benazepril Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amr Marawan, M.D. [2], Ahmed Zaghw, M.D. [3], Abdurahman Khalil, M.D. [4], Sheng Shi, M.D. [5], Jesus Rosario Hernandez, M.D. [6] Synonyms / Brand Names: Lotensin® # Disclaimer WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer here. # Black Box Warning # Overview Benazepril is an angiotensin converting enzyme inhibitor drug that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cough, dizziness, fatigue, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial dose (not receiving a diuretic): Benazepril 10 mg PO qd - Initial dose (concurrent diuretic use): the diuretic should be discontinued 2 to 3 days prior to initiating Benazepril to reduce the likelihood of hypotension. If blood pressure is not controlled with Benazepril alone, diuretic should be resumed and Benazepril 5 mg PO qd should be used. - Maintenance dose:Benazepril 20—40 mg PO qd or Benazepril 10—20 mg PO bid (MAX 80 mg/day) - The divided regimen was more effective in controlling trough (pre-dosing) blood pressure than the same dose given as a once-daily regimen. Dosage adjustment should be based on measurement of peak (2-6 hours after dosing) and trough responses. If a once-daily regimen does not give adequate trough response, an increase in dosage or divided administration should be considered. - If blood pressure is not controlled with Benazepril alone, a diuretic can be added. - Concomitant administration of Benazepril with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium. - Dosing Information - Initial dose (for creatinine clearance <30 mL/min/1.73 m2 or Cr >3 mg/dL):Benazepril 5 mg PO qd - Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg gs.[1] ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Cardiology (ACC) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level A - Recommendation - In all patients with a recent or remote history of MI or ACS and reduced EF, ACE inhibitors should be used to prevent symptomatic HF and reduce mortality.[2] - Developed by: American College of Cardiology (ACC) and American Heart Association (AHA) - Class of Recommendation: Class I - Level of Evidence: Level A - Recommendation - An angiotensin-converting enzyme (ACE) inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction (EF) less than or equal to 0.40, unless contraindicated.[3] ### Non–Guideline-Supported Use - Dosing Information - Benazepril 10 mg PO qd[4][5] - Dosing Information - Benazepril 10 mg PO qd[4][5] - Dosing Information - Benazepril 20 mg PO qd for 2 weeks, followed by Benazepril 40 mg qd or combination of Benazepril 40 mg PO qd and amlodipine 5 mg PO qd[6] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Initial dose: Benazepril 0.2 mg/kg PO qd (for pediatric patients above the age of 6 years) - Benazepril is not advised for children below the age of 6 years and in pediatric patients with glomerular filtration rate <30 mL. - For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths for Benazepril, follow the suspension preparation instructions to administer Benazepril HCl as a suspension. - Dosing Information - Initial dose (for creatinine clearance <30 mL/min/1.73 m2 or Cr >3 mg/dL): Benazepril 5 mg PO qd - Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg. ## Off-Label Use and Dosage (Pediatric) There is limited information about Off-Label Use and Dosage of Benazepril tablet in pediatric patients. # Contraindications - Hypersensitivity to Benazepril or to any other ACE inhibitor - History of angioedema with or without previous ACE inhibitor treatment # Warnings - Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Benazepril) may be subject to a variety of adverse reactions, some of them serious. - Head and Neck Angioedema - Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received Benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Benazepril should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptly administered. - Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks. - Intestinal Angioedema - Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. - Anaphylactoid Reactions During Desensitization - Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. - Anaphylactoid Reactions During Membrane Exposure - Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States). - Benazepril can cause symptomatic hypotension. Like other ACE inhibitors, Benazepril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume-and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume-and/or salt-depletion should be corrected before initiating therapy with Benazepril. - In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, Benazepril therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of benazepril or diuretic is increased. - If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Benazepril treatment usually can be continued following restoration of blood pressure and volume. - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benazepril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benazepril, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Benazepril for hypotension, oliguria, and hyperkalemia. - No teratogenic effects of Benazepril were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose. - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. # Adverse Reactions ## Clinical Trials Experience - Benazepril has been evaluated for safety in over 6000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was comparable in Benazepril and placebo patients. - The reported side effects were generally mild and transient, and there was no relation between side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg. Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with Benazepril and in 3% of patients treated with placebo. - The most common reasons for discontinuation were headache (0.6%) and cough (0.5%) - The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Benazepril are shown below. - Other adverse experiences reported in controlled clinical trials (in less than 1% of Benazepril patients or with less than 1% difference in incidence between Benazepril or placebo treatment), and rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug use is uncertain): - Dermatologic - Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing. - Gastrointestinal - Nausea, pancreatitis, constipation, gastritis, vomiting, and melena. - Hematologic - Thrombocytopenia and hemolytic anemia. - Neurologic and Psychiatric - Anxiety, decreased libido, hypertonia, insomnia, nervousness, and paresthesia. - Other - Fatigue, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination, infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating. - Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors. - Clinical Laboratory Test Findings - Hemoglobin - Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were rare, occurring in only 1 of 2,014 patients receiving Benazepril alone and in 1 of 1,357 patients receiving Benazepril plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin. - Other (causal relationships unknown) - Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes have been reported, as have scattered incidents of hyponatremia, electrocardiographic changes, eosinophilia, and proteinuria. - Pediatric Patients - The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients. ## Postmarketing Experience - FDA Package Insert for Benazepril contains no information regarding Postmarketing Experience. # Drug Interactions Diuretics - Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Benazepril. The possibility of hypotensive effects with Benazepril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Benazepril. If this is not possible, the starting dose should be reduced. Potassium supplements and potassium-sparing diuretics - Concomitant use with Benazepril may effect potassium levels. Monitor potassium periodically. Oral anticoagulants - Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants. Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including Benazepril) during therapy with lithium. Monitor lithium levels when used concomitantly with Benazepril. Gold - Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Anti-diabetics - In rare cases, diabetic patients receiving an ACE inhibitor (including Benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly. NSAID\|Non-steroidal anti-inflammatory drugs (NSAIDs) including selective COX-2 inhibitor\|cyclooxygenase-2 inhibitors (COX-2 inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including Benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Benazepril and NSAID therapy. - The antihypertensive effect of ACE inhibitors, including Benazepril, may be attenuated by NSAIDs. Miscellaneous - Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important adverse interactions. Benazepril, like other ACE inhibitors, has had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system. - The pharmacokinetics of Benazepril are not affected by the following drugs: hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of Benazepril does not substantially affect the pharmacokinetics of these medications (cimetidine kinetics were not studied). # Use in Specific Populations ### Pregnancy - Fetal toxicity - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benazepril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benazepril, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Benazepril for hypotension, oliguria, and hyperkalemia. - No teratogenic effects of Benazepril were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose. ### Labor and Delivery - FDA Package Insert for Benazepril contains no information regarding Labor and Delivery. ### Nursing Mothers - Minimal amounts of unchanged Benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with Benazepril. A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of Benazepril and benazeprilat. ### Pediatric Use - Neonates with a history of in utero exposure to Benazepril - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited. - The antihypertensive effects of Benazepril have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age . The pharmacokinetics of Benazepril have been evaluated in pediatric patients 6 to 16 years of age . Benazepril was generally well tolerated and adverse effects were similar to those described in adults.The long-term effects of Benazepril on growth and development have not been studied. Infants below the age of 1 year should not be given Benazepril because of the risk of effects on kidney development. - Treatment with Benazepril is not recommended in pediatric patients less than 6 years of age , and in children with glomerular filtration rate <30 mL/min as there are insufficient data available to support a dosing recommendation in these groups. ### Geriatric Use - Of the total number of patients who received Benazepril in U.S. clinical studies of Benazepril, 18% were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ### Gender FDA Package Insert for Benazepril contains no information regarding Gender. ### Race FDA Package Insert for Benazepril contains no information regarding Race. ### Renal Impairment - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including Benazepril, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In a small study of hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, treatment with Benazepril was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of Benazepril or diuretic therapy, or both. When such patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Benazepril has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of Benazepril and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function. ### Hepatic Impairment - Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. ### Carcinogenesis, Mutagenesis, Impairment of Fertility - No evidence of carcinogenicity was found when Benazepril was administered to rats and mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body weights, this dose is 110 times the maximum recommended human dose. When compared on the basis of body surface areas, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg). - No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. - In doses of 50-500 mg/kg/day (6-60 times the maximum recommended human dose based on mg/m2 comparison and 37-375 times the maximum recommended human dose based on a mg/kg comparison), Benazepril had no adverse effect on the reproductive performance of male and female rats. ### Immunocompromised Patients FDA Package Insert for Benazepril contains no information regarding Immunocompromised Patients. ### Miscellaneous Hyperkalemia - In clinical trials, hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal) occurred in approximately 1% of hypertensive patients receiving Benazepril. In most cases, these were isolated values which resolved despite continued therapy. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Benazepril. Cough - Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia - In patients undergoing surgery or during anesthesia with agents that produce hypotension, Benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. # Administration and Monitoring ### Administration - Oral - Preparation of suspension (for 150 mL of a 2 mg/mL suspension) - Add 75 mL of Ora-Plus® oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen Benazepril 20 mg tablets, and shake for at least 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 75 mL of Ora-Sweet® oral syrup vehicle to the bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap closure. Shake the suspension before each use. ### Monitoring Geriatric Use - Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Overdose - Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure. Renal Artery Stenosis - When hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy. Use of Potassium Supplements and Potassium-Sparing Diuretics - Concomitant potassium supplements and potassium-sparing diuretics use with Benazepril may effect potassium levels. Monitor potassium periodically. Use of Lithium - Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including Benazepril) during therapy with lithium. Monitor lithium levels when used concomitantly with Benazepril. Use of Anti-Diabetics - In rare cases, diabetic patients receiving an ACE inhibitor (including Benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly. Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Benazepril and NSAID therapy. # IV Compatibility FDA Package Insert for Benazepril contains no information regarding IV Compatibility. # Overdosage ## Acute Overdose ### Signs and Symptoms - Human overdoses of Benazepril have not been reported, but the most common manifestation of human Benazepril overdosage is likely to be hypotension, which can be associated with electrolyte disturbances and renal failure. ### Management - Laboratory determinations of serum levels of Benazepril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Benazepril overdose. - No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Benazepril and its metabolites. Benazepril is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see Warnings). - Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of Benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of Benazepril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Benazepril overdose by infusion of normal saline solution. - If ingestion is recent, activated charcoal should be considered. Gastric decontamination (e.g., vomiting, gastric lavage) may be considered in individual cases, in the early period after ingestion. - Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure. - In the case of marked hypotension, physiological saline solution should be administered intravenously; depending on the clinical situation the use of vasopressors (e.g., catecholamines i.v.) may be considered. ## Chronic Overdose ### Signs and Symptoms - FDA Package Insert for Benazepril contains no information regarding Signs and Symptoms in Chronic Overdose. ### Management - FDA Package Insert for Benazepril contains no information regarding Management in Chronic Overdose. # Pharmacology ## Mechanism of Action - Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. - Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with Benazepril alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with Benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium. - Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine. - ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Benazepril remains to be elucidated. - While the mechanism through which Benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Benazepril has an antihypertensive effect even in patients with low-renin hypertension. ## Structure - Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol. Its chemical name is benazepril 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride. - Its empirical formula is C24H28N2O5•HCl, and its molecular weight is 460.96. - Benazeprilat, the active metabolite of Benazepril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group. - Benazepril is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of benazepril hydrochloride for oral administration. The inactive ingredients are colloidal silicon dioxide, crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80, propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide. ## Pharmacodynamics - Single and multiple doses of 10 mg or more of Benazepril cause inhibition of plasma ACE activity by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg dose. ## Pharmacokinetics - Following oral administration of Benazepril, peak plasma concentrations of Benazepril are reached within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract. - Cleavage of the ester group (primarily in the liver) converts Benazepril to its active metabolite, benazeprilat. Peak plasma concentrations of benazeprilat are reached 1-2 hours after drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein binding of Benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-23.6 µmol/L). - Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE inhibitory activity than Benazepril, and to the glucuronide conjugates of Benazepril and benazeprilat. Only trace amounts of an administered dose of Benazepril can be recovered in the urine as unchanged Benazepril, while about 20% of the dose is excreted as benazeprilat, 4% as benazepril glucuronide, and 8% as benazeprilat glucuronide. - The kinetics of Benazepril are approximately dose-proportional within the dosage range of 10-80 mg. - In adults, the effective half-life of accumulation of benazeprilat following multiple dosing of benazepril hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily. - The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively. - Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance. - In patients with renal insufficiency, the disposition of benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance <30 mL/min, peak benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady state may be delayed (see Adult Indications and Dosage). - When dialysis was started 2 hours after ingestion of 10 mg of Benazepril, approximately 6% of benazeprilat was removed in 4 hours of dialysis. The parent compound, Benazepril, was not detected in the dialysate. - In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat are essentially unaltered. The pharmacokinetics of Benazepril and benazeprilat do not appear to be influenced by age. - In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of Benazepril (0.1 to 0.5 mg/kg), the clearance of benazeprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of benazeprilat in pediatric patients was around 5 hours, one-third that observed in adults. ## Nonclinical Toxicology - FDA Package Insert for Benazepril contains no information regarding Nonclinical Toxicology. # Clinical Studies - In single-dose studies, Benazepril lowered blood pressure within 1 hour, with peak reductions achieved 2-4 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 6-12/4-7 mmHg. The trough values represent reductions of about 50% of that seen at peak. - Four dose-response studies using once-daily dosing were conducted in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective once-daily dose of Benazepril was 10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10-80 mg). In studies comparing the same daily dose of Benazepril given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen. - The antihypertensive effects of Benazepril were not appreciably different in patients receiving high- or low-sodium diets. - In normal human volunteers, single doses of Benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate. - Use of Benazepril in combination with thiazide diuretics gives a blood-pressure-lowering effect greater than that seen with either agent alone. By blocking the renin-angiotensin-aldosterone axis, administration of Benazepril tends to reduce the potassium loss associated with the diuretic. - In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or 0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or Benazepril and were followed up for an additional two weeks. At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg more than in children on Benazepril. No dose-response was observed for the three doses. # How Supplied - Benazepril is available in tablets of 5 mg, 10 mg, 20 mg, and 40 mg, packaged with a desiccant in bottles of 100 tablets. - Each tablet is imprinted with Benazepril on one side and the tablet strength (“5,” “10,” “20,” or “40”) on the other. - National Drug Code (NDC): - Storage - Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP). - Manufactured by - Novartis Pharmaceuticals Corporation, Suffern, New York 10901 - Distributed by - Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 # Images ## Drug Images ## Package and Label Display Panel # Patient Information ## Patient Information from FDA - Pregnancy - Female patients of childbearing age should be told about the consequences of exposure to Benazepril during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. - Angioedema - Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician. - Symptomatic Hypotension - Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to the prescribing physician. Patients should be told that if syncope occurs, Benazepril should be discontinued until the prescribing physician has been consulted. - All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. - Hyperkalemia - Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. - Neutropenia - Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia. ## Patient Information from NLM For patient information about benazepril from NLM, click here. # Precautions with Alcohol Alcohol-Benazepril interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Lotensin® # Look-Alike Drug Names Benazepril — Benadryl® Lotensin® — Latensin®, Lioresal®, Lovastatin # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Benazepril
9a3644346425664300ed0e6d7955ad5ee146d313	wikidoc	Probenecid	Probenecid # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Probenecid is an antigout, uricosuric and renal tubular transport blocking agent. that is FDA approved for the treatment of hyperuricemia associated with gout and gouty arthritis. Common adverse reactions include headache, dizziness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Therapy with probenecid should not be started until an acute gouty attack has subsided. However, if an acute attack is precipitated during therapy, probenecid may be continued without changing the dosage, and full therapeutic dosage of colchicine, or other appropriate therapy, should be given to control the acute attack. Dosage: The recommended adult dosage is 250 mg (½ probenecid tablet), twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter. - Dosage: The recommended adult dosage is 250 mg (½ probenecid tablet), twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter. - Some degree of renal impairment may be present in patients with gout. A daily dosage of 1000 mg may be adequate. However, if necessary, the daily dosage may be increased by 500 mg increments every 4 weeks within tolerance (and usually not above 2000 mg per day) if symptoms of gouty arthritis are not controlled or the 24 hour uric acid excretion is not above 700 mg. As noted, probenecid may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mg mL/minute or less. - Gastric intolerance may be indicative of overdosage, and may be corrected by decreasing the dosage. - As uric acid tends to crystallize out of an acid urine, a liberal fluid intake is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g daily ), or potassium citrate (7.5 g daily) to maintain an alkaline urine. - Alkalization of the urine is recommended until the serum urate level returns to normal limits and tophaceous deposits disappear, i.e., during the period when urinary excretion of uric acid is at high level. Thereafter, alkalization of the urine and the usual restriction of purine-producing foods may be somewhat relaxed. Probenecid should be continued at the dosage that will maintain normal serum urate levels. When acute attacks have been absent for 6 months or more and serum urate levels remain within normal limits, the daily dosage may be decreased by 500 mg every 6 months. The maintenance dosage should not be reduced to the point where serum urate levels tend to rise. - Recommended by the Center of Disease Control, U.S Department of Health and Human Services, Public Health Service (Morbidity and Mortality Weekly Report Supplement, Volume 34, Number 4S, October 18, 1985). In uncomplicated gonococcal infections in men and women (urethral, cervical, rectal), 1 g of probenecid should be given orally with 4.8 million units of aqueous procaine penicillin G² (given IM), or 3 g of amoxicillin² (given orally), or 3.5 g of ampicillin² (given orally). - Adults: The recommended dosage is 2000 mg (4 tablets of probenecid) daily in divided doses. This dosage should be reduced in older patients in whom renal impairment may be present. - Children: 2-14 years of age: Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface). Maintenance Dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per day, divided into 4 doses. For children weighing more than 50 kg (110 lb) the adult dosage is recommended. Probenecid is contraindicated in children under 2 years of age. - Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface). - Maintenance Dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per day, divided into 4 doses. For children weighing more than 50 kg (110 lb) the adult dosage is recommended. Probenecid is contraindicated in children under 2 years of age. - For children weighing more than 50 kg (110 lb) the adult dosage is recommended. - Probenecid is contraindicated in children under 2 years of age. The PSP excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about one-fifth the normal rate when dosage of probenecid is adequate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Probenecid in adult patients. ### Non–Guideline-Supported Use - Cidofovir: 2g PO administered 3 hours before administering cidofovir; probenecid 1g PO should be given at 2 and 8 hours after cidofovir has been infused. In total, 4g PO probenecid per cidofovir infusion. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Therapy with probenecid should not be started until an acute gouty attack has subsided. However, if an acute attack is precipitated during therapy, probenecid may be continued without changing the dosage, and full therapeutic dosage of colchicine, or other appropriate therapy, should be given to control the acute attack. Dosage: The recommended adult dosage is 250 mg (½ probenecid tablet), twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter. - Dosage: The recommended adult dosage is 250 mg (½ probenecid tablet), twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter. - Some degree of renal impairment may be present in patients with gout. A daily dosage of 1000 mg may be adequate. However, if necessary, the daily dosage may be increased by 500 mg increments every 4 weeks within tolerance (and usually not above 2000 mg per day) if symptoms of gouty arthritis are not controlled or the 24 hour uric acid excretion is not above 700 mg. As noted, probenecid may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mg mL/minute or less. - Gastric intolerance may be indicative of overdosage, and may be corrected by decreasing the dosage. - As uric acid tends to crystallize out of an acid urine, a liberal fluid intake is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g daily ), or potassium citrate (7.5 g daily) to maintain an alkaline urine. - Alkalization of the urine is recommended until the serum urate level returns to normal limits and tophaceous deposits disappear, i.e., during the period when urinary excretion of uric acid is at high level. Thereafter, alkalization of the urine and the usual restriction of purine-producing foods may be somewhat relaxed. Probenecid should be continued at the dosage that will maintain normal serum urate levels. When acute attacks have been absent for 6 months or more and serum urate levels remain within normal limits, the daily dosage may be decreased by 500 mg every 6 months. The maintenance dosage should not be reduced to the point where serum urate levels tend to rise. - Recommended by the Center of Disease Control, U.S Department of Health and Human Services, Public Health Service (Morbidity and Mortality Weekly Report Supplement, Volume 34, Number 4S, October 18, 1985). In uncomplicated gonococcal infections in men and women (urethral, cervical, rectal), 1 g of probenecid should be given orally with 4.8 million units of aqueous procaine penicillin G² (given IM), or 3 g of amoxicillin² (given orally), or 3.5 g of ampicillin² (given orally). - Adults: The recommended dosage is 2000 mg (4 tablets of probenecid) daily in divided doses. This dosage should be reduced in older patients in whom renal impairment may be present. - Children: 2-14 years of age: Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface). Maintenance Dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per day, divided into 4 doses. For children weighing more than 50 kg (110 lb) the adult dosage is recommended. Probenecid is contraindicated in children under 2 years of age. - Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface). - Maintenance Dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per day, divided into 4 doses. For children weighing more than 50 kg (110 lb) the adult dosage is recommended. Probenecid is contraindicated in children under 2 years of age. - For children weighing more than 50 kg (110 lb) the adult dosage is recommended. - Probenecid is contraindicated in children under 2 years of age. The PSP excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about one-fifth the normal rate when dosage of probenecid is adequate. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Probenecid in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Probenecid in pediatric patients. # Contraindications - Hypersensitivity to probenecid. - Children under 2 years of age. - Not recommended in persons with known blood dyscrasias or uric acid kidney stones. - Therapy with probenecid should not be started until an acute gouty attack has subsided. # Warnings - Exacerbation of gout following therapy with probenecid may occur; in such cases colchicine or other appropriate therapy is advisable. - Probenecid increases plasma concentrations of methotrexate in both animals and humans. In animal studies, increased methotrexate toxicity has been reported. If probenecid is given with methotrexate, the dosage of methotrexate should be reduced and serum levels may need to be monitored. - In patients on probenecid the use of salicylates in either small or large doses is contraindicated because it antagonizes the uricosuric action of probenecid. The biphasic action of salicylates in the renal tubules accounts for the so-called “paradoxical effect” of uricosuric agents. In patients on probenecid who require a mild analgesic agent the use of acetaminophen rather than small doses of salicylates would be preferred. - Rarely, severe allergic reactions and anaphylaxis have been reported with the use of probenecid. Most of these have been reported to occur within several hours after readministration following prior usage of the drug. - The appearance of hypersensitivity reactions requires cessation of therapy with probenecid. - Use in Pregnancy: Probenecid crosses the placenta barrier and appears in cord blood. The use of any drug in women of childbearing potential requires that the anticipated benefit be weighed against the possible hazards. - Probenecid crosses the placenta barrier and appears in cord blood. The use of any drug in women of childbearing potential requires that the anticipated benefit be weighed against the possible hazards. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions have been observed and within each category are listed in order of decreasing severity. - Headache - Dizziness - Precipitation of acute gouty arthritis. - Hepatic necrosis - Vomiting - Nausea - Anorexia - Sore gums - Nephrotic syndrome - Uric acid stones with or without hematuria - Renal colic - Costovertebral pain - Urinary frequency - Anaphylaxis - Fever - Urticaria - Pruritus - Aplastic anemia - Leukopenia - Hemolytic anemia which in some patients could be related to genetic deficiency of glucose-6-phosphate dehydrogenase in red blood cells - Anemia - Dermatitis - Alopecia - Flushing ## Postmarketing Experience There is limited information regarding Probenecid Postmarketing Experience in the drug label. # Drug Interactions - When probenecid is used to elevate plasma concentrations of penicillin or other beta-lactams, or when such drugs are given to patients taking probenecid therapeutically, high plasma concentrations of the other drug may increase the incidence of adverse reactions associated with that drug. In the case of penicillin or other beta-lactams, psychic disturbances have been reported. - The use of salicylates antagonizes the uricosuric action of probenecid. The uricosuric action of probenecid is also antagonized by pyrazinamide. - Probenecid produces an insignificant increase in free sulfonamide plasma concentrations, but a significant increase in total sulfonamide plasma levels. Since probenecid decreases the renal excretion of conjugated sulfonamides, plasma concentrations of the latter should be determined from time to time when sulfonamide and probenecid are coadministered for prolonged periods. Probenecid may prolong or enhance the action of oral sulfonylureas and thereby increase the risk of hypoglycemia. - It has been reported that patients receiving probenecid require significantly less thiopental for induction of anesthesia. In addition, ketamine and thiopental anesthesia were significantly prolonged in rats receiving probenecid. - The concomitant administration of probenecid increases the mean plasma elimination half-life of a number of drugs which can lead to increased plasma concentrations. These include agents such as indomethacin, acetaminophen, naproxen, ketoprofen, meclofenamate, lorazepam, and rifampin. Although the clinical significance of this observation has not been established, a lower dosage of the drug may be required to produce a therapeutic effect, and increases a dosage of the drug in question should be made cautiously and in small increments when probenecid is being coadministered. Although specific instances of toxicity due to this potential interaction have not been observed to date, physicians should be alert to this possibility. - Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest reduction in the uricosuric action of probenecid, which probably is not significant under most circumstances. - In animals and in humans, probenecid has been reported to increase plasma concentrations of methotrexate - Falsely high readings for theophylline have been reported in an in vitro study, using the Schack and Waxler technique, when therapeutic concentrations of theophylline and probenecid were added to human plasma. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Probenecid crosses the placenta barrier and appears in cord blood. The use of any drug in women of childbearing potential requires that the anticipated benefit be weighed against the possible hazards. Pregnancy Category (AUS): B2 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Probenecid in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Probenecid during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Probenecid in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Probenecid in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Probenecid in geriatric settings. ### Gender There is no FDA guidance on the use of Probenecid with respect to specific gender populations. ### Race There is no FDA guidance on the use of Probenecid with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Probenecid in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Probenecid in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Probenecid in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Probenecid in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Probenecid Administration in the drug label. ### Monitoring There is limited information regarding Probenecid Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Probenecid and IV administrations. # Overdosage There is limited information regarding Probenecid overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Probenecid is a uricosuric and renal tubular blocking agent. It inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits. - Probenecid inhibits the tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is given. A 2-fold to 4-fold elevation has been demonstrated for various penicillins. - Probenecid also has been reported to inhibit the renal transport of many other compounds including aminohippuric acid (PAH), aminosalicylic acid (PAS), indomethacin, sodium iodomethamate and related iodinated organic acids, 17 –ketosteroids, pantothenic acid, phenolsulfonphthalein (PSP), sulfonamides, and sulfonylureas. ## Structure - The chemical name for probenecid is 4- benzoic acid. It has the following structural formula: ## Pharmacodynamics There is limited information regarding Probenecid Pharmacodynamics in the drug label. ## Pharmacokinetics - Probenecid decreases both hepatic and renal excretion of sulfobromophtalein (BSP). The tubular reabsorption of phosphorus is inhibited in hypoparathyroid but not in euparathyroid individuals. Probenecid does not influence plasma concentrations of salicylates, nor the excretion of streptomycin, chloramphenicol, chlortetracycline, oxytetracycline, or neomycin. ## Nonclinical Toxicology There is limited information regarding Probenecid Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Probenecid Clinical Studies in the drug label. # How Supplied - Probenecid Tablets, USP are available containing 500 mg of Probenecid, USP. - The tablets are capsule shaped, film-coated yellow, debossed LCI on one side and 1367 on the other side. They are available as follows: NDC 10135-541-10 bottles of 1000 tablets - NDC 10135-541-10 bottles of 1000 tablets ## Storage Store at 20˚ to 25˚c (68˚-77˚f). Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Probenecid Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Probenecid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Benemid - Probalan # Look-Alike Drug Names There is limited information regarding Probenecid Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Probenecid Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Probenecid is an antigout, uricosuric and renal tubular transport blocking agent. that is FDA approved for the treatment of hyperuricemia associated with gout and gouty arthritis. Common adverse reactions include headache, dizziness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Therapy with probenecid should not be started until an acute gouty attack has subsided. However, if an acute attack is precipitated during therapy, probenecid may be continued without changing the dosage, and full therapeutic dosage of colchicine, or other appropriate therapy, should be given to control the acute attack. Dosage: The recommended adult dosage is 250 mg (½ probenecid tablet), twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter. - Dosage: The recommended adult dosage is 250 mg (½ probenecid tablet), twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter. - Some degree of renal impairment may be present in patients with gout. A daily dosage of 1000 mg may be adequate. However, if necessary, the daily dosage may be increased by 500 mg increments every 4 weeks within tolerance (and usually not above 2000 mg per day) if symptoms of gouty arthritis are not controlled or the 24 hour uric acid excretion is not above 700 mg. As noted, probenecid may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mg mL/minute or less. - Gastric intolerance may be indicative of overdosage, and may be corrected by decreasing the dosage. - As uric acid tends to crystallize out of an acid urine, a liberal fluid intake is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g daily ), or potassium citrate (7.5 g daily) to maintain an alkaline urine. - Alkalization of the urine is recommended until the serum urate level returns to normal limits and tophaceous deposits disappear, i.e., during the period when urinary excretion of uric acid is at high level. Thereafter, alkalization of the urine and the usual restriction of purine-producing foods may be somewhat relaxed. Probenecid should be continued at the dosage that will maintain normal serum urate levels. When acute attacks have been absent for 6 months or more and serum urate levels remain within normal limits, the daily dosage may be decreased by 500 mg every 6 months. The maintenance dosage should not be reduced to the point where serum urate levels tend to rise. - Recommended by the Center of Disease Control, U.S Department of Health and Human Services, Public Health Service (Morbidity and Mortality Weekly Report Supplement, Volume 34, Number 4S, October 18, 1985). In uncomplicated gonococcal infections in men and women (urethral, cervical, rectal), 1 g of probenecid should be given orally with 4.8 million units of aqueous procaine penicillin G² (given IM), or 3 g of amoxicillin² (given orally), or 3.5 g of ampicillin² (given orally). - Adults: The recommended dosage is 2000 mg (4 tablets of probenecid) daily in divided doses. This dosage should be reduced in older patients in whom renal impairment may be present. - Children: 2-14 years of age: Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface). Maintenance Dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per day, divided into 4 doses. For children weighing more than 50 kg (110 lb) the adult dosage is recommended. Probenecid is contraindicated in children under 2 years of age. - Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface). - Maintenance Dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per day, divided into 4 doses. For children weighing more than 50 kg (110 lb) the adult dosage is recommended. Probenecid is contraindicated in children under 2 years of age. - For children weighing more than 50 kg (110 lb) the adult dosage is recommended. - Probenecid is contraindicated in children under 2 years of age. The PSP excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about one-fifth the normal rate when dosage of probenecid is adequate. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Probenecid in adult patients. ### Non–Guideline-Supported Use - Cidofovir: 2g PO administered 3 hours before administering cidofovir; probenecid 1g PO should be given at 2 and 8 hours after cidofovir has been infused. In total, 4g PO probenecid per cidofovir infusion. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Therapy with probenecid should not be started until an acute gouty attack has subsided. However, if an acute attack is precipitated during therapy, probenecid may be continued without changing the dosage, and full therapeutic dosage of colchicine, or other appropriate therapy, should be given to control the acute attack. Dosage: The recommended adult dosage is 250 mg (½ probenecid tablet), twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter. - Dosage: The recommended adult dosage is 250 mg (½ probenecid tablet), twice a day for one week, followed by 500 mg (1 tablet) twice a day thereafter. - Some degree of renal impairment may be present in patients with gout. A daily dosage of 1000 mg may be adequate. However, if necessary, the daily dosage may be increased by 500 mg increments every 4 weeks within tolerance (and usually not above 2000 mg per day) if symptoms of gouty arthritis are not controlled or the 24 hour uric acid excretion is not above 700 mg. As noted, probenecid may not be effective in chronic renal insufficiency particularly when the glomerular filtration rate is 30 mg mL/minute or less. - Gastric intolerance may be indicative of overdosage, and may be corrected by decreasing the dosage. - As uric acid tends to crystallize out of an acid urine, a liberal fluid intake is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g daily ), or potassium citrate (7.5 g daily) to maintain an alkaline urine. - Alkalization of the urine is recommended until the serum urate level returns to normal limits and tophaceous deposits disappear, i.e., during the period when urinary excretion of uric acid is at high level. Thereafter, alkalization of the urine and the usual restriction of purine-producing foods may be somewhat relaxed. Probenecid should be continued at the dosage that will maintain normal serum urate levels. When acute attacks have been absent for 6 months or more and serum urate levels remain within normal limits, the daily dosage may be decreased by 500 mg every 6 months. The maintenance dosage should not be reduced to the point where serum urate levels tend to rise. - Recommended by the Center of Disease Control, U.S Department of Health and Human Services, Public Health Service (Morbidity and Mortality Weekly Report Supplement, Volume 34, Number 4S, October 18, 1985). In uncomplicated gonococcal infections in men and women (urethral, cervical, rectal), 1 g of probenecid should be given orally with 4.8 million units of aqueous procaine penicillin G² (given IM), or 3 g of amoxicillin² (given orally), or 3.5 g of ampicillin² (given orally). - Adults: The recommended dosage is 2000 mg (4 tablets of probenecid) daily in divided doses. This dosage should be reduced in older patients in whom renal impairment may be present. - Children: 2-14 years of age: Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface). Maintenance Dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per day, divided into 4 doses. For children weighing more than 50 kg (110 lb) the adult dosage is recommended. Probenecid is contraindicated in children under 2 years of age. - Initial dose: 25 mg/kg body weight (or 0.7 g/square meter body surface). - Maintenance Dose: 40 mg/kg body weight (or 1.2 g/square meter body surface) per day, divided into 4 doses. For children weighing more than 50 kg (110 lb) the adult dosage is recommended. Probenecid is contraindicated in children under 2 years of age. - For children weighing more than 50 kg (110 lb) the adult dosage is recommended. - Probenecid is contraindicated in children under 2 years of age. The PSP excretion test may be used to determine the effectiveness of probenecid in retarding penicillin excretion and maintaining therapeutic levels. The renal clearance of PSP is reduced to about one-fifth the normal rate when dosage of probenecid is adequate. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Probenecid in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Probenecid in pediatric patients. # Contraindications - Hypersensitivity to probenecid. - Children under 2 years of age. - Not recommended in persons with known blood dyscrasias or uric acid kidney stones. - Therapy with probenecid should not be started until an acute gouty attack has subsided. # Warnings - Exacerbation of gout following therapy with probenecid may occur; in such cases colchicine or other appropriate therapy is advisable. - Probenecid increases plasma concentrations of methotrexate in both animals and humans. In animal studies, increased methotrexate toxicity has been reported. If probenecid is given with methotrexate, the dosage of methotrexate should be reduced and serum levels may need to be monitored. - In patients on probenecid the use of salicylates in either small or large doses is contraindicated because it antagonizes the uricosuric action of probenecid. The biphasic action of salicylates in the renal tubules accounts for the so-called “paradoxical effect” of uricosuric agents. In patients on probenecid who require a mild analgesic agent the use of acetaminophen rather than small doses of salicylates would be preferred. - Rarely, severe allergic reactions and anaphylaxis have been reported with the use of probenecid. Most of these have been reported to occur within several hours after readministration following prior usage of the drug. - The appearance of hypersensitivity reactions requires cessation of therapy with probenecid. - Use in Pregnancy: Probenecid crosses the placenta barrier and appears in cord blood. The use of any drug in women of childbearing potential requires that the anticipated benefit be weighed against the possible hazards. - Probenecid crosses the placenta barrier and appears in cord blood. The use of any drug in women of childbearing potential requires that the anticipated benefit be weighed against the possible hazards. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions have been observed and within each category are listed in order of decreasing severity. - Headache - Dizziness - Precipitation of acute gouty arthritis. - Hepatic necrosis - Vomiting - Nausea - Anorexia - Sore gums - Nephrotic syndrome - Uric acid stones with or without hematuria - Renal colic - Costovertebral pain - Urinary frequency - Anaphylaxis - Fever - Urticaria - Pruritus - Aplastic anemia - Leukopenia - Hemolytic anemia which in some patients could be related to genetic deficiency of glucose-6-phosphate dehydrogenase in red blood cells - Anemia - Dermatitis - Alopecia - Flushing ## Postmarketing Experience There is limited information regarding Probenecid Postmarketing Experience in the drug label. # Drug Interactions - When probenecid is used to elevate plasma concentrations of penicillin or other beta-lactams, or when such drugs are given to patients taking probenecid therapeutically, high plasma concentrations of the other drug may increase the incidence of adverse reactions associated with that drug. In the case of penicillin or other beta-lactams, psychic disturbances have been reported. - The use of salicylates antagonizes the uricosuric action of probenecid. The uricosuric action of probenecid is also antagonized by pyrazinamide. - Probenecid produces an insignificant increase in free sulfonamide plasma concentrations, but a significant increase in total sulfonamide plasma levels. Since probenecid decreases the renal excretion of conjugated sulfonamides, plasma concentrations of the latter should be determined from time to time when sulfonamide and probenecid are coadministered for prolonged periods. Probenecid may prolong or enhance the action of oral sulfonylureas and thereby increase the risk of hypoglycemia. - It has been reported that patients receiving probenecid require significantly less thiopental for induction of anesthesia. In addition, ketamine and thiopental anesthesia were significantly prolonged in rats receiving probenecid. - The concomitant administration of probenecid increases the mean plasma elimination half-life of a number of drugs which can lead to increased plasma concentrations. These include agents such as indomethacin, acetaminophen, naproxen, ketoprofen, meclofenamate, lorazepam, and rifampin. Although the clinical significance of this observation has not been established, a lower dosage of the drug may be required to produce a therapeutic effect, and increases a dosage of the drug in question should be made cautiously and in small increments when probenecid is being coadministered. Although specific instances of toxicity due to this potential interaction have not been observed to date, physicians should be alert to this possibility. - Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest reduction in the uricosuric action of probenecid, which probably is not significant under most circumstances. - In animals and in humans, probenecid has been reported to increase plasma concentrations of methotrexate - Falsely high readings for theophylline have been reported in an in vitro study, using the Schack and Waxler technique, when therapeutic concentrations of theophylline and probenecid were added to human plasma. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Probenecid crosses the placenta barrier and appears in cord blood. The use of any drug in women of childbearing potential requires that the anticipated benefit be weighed against the possible hazards. Pregnancy Category (AUS): B2 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Probenecid in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Probenecid during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Probenecid in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Probenecid in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Probenecid in geriatric settings. ### Gender There is no FDA guidance on the use of Probenecid with respect to specific gender populations. ### Race There is no FDA guidance on the use of Probenecid with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Probenecid in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Probenecid in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Probenecid in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Probenecid in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Probenecid Administration in the drug label. ### Monitoring There is limited information regarding Probenecid Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Probenecid and IV administrations. # Overdosage There is limited information regarding Probenecid overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Probenecid is a uricosuric and renal tubular blocking agent. It inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits. - Probenecid inhibits the tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is given. A 2-fold to 4-fold elevation has been demonstrated for various penicillins. - Probenecid also has been reported to inhibit the renal transport of many other compounds including aminohippuric acid (PAH), aminosalicylic acid (PAS), indomethacin, sodium iodomethamate and related iodinated organic acids, 17 –ketosteroids, pantothenic acid, phenolsulfonphthalein (PSP), sulfonamides, and sulfonylureas. ## Structure - The chemical name for probenecid is 4-[(dipropylamino) sulfony1] benzoic acid. It has the following structural formula: ## Pharmacodynamics There is limited information regarding Probenecid Pharmacodynamics in the drug label. ## Pharmacokinetics - Probenecid decreases both hepatic and renal excretion of sulfobromophtalein (BSP). The tubular reabsorption of phosphorus is inhibited in hypoparathyroid but not in euparathyroid individuals. Probenecid does not influence plasma concentrations of salicylates, nor the excretion of streptomycin, chloramphenicol, chlortetracycline, oxytetracycline, or neomycin. ## Nonclinical Toxicology There is limited information regarding Probenecid Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Probenecid Clinical Studies in the drug label. # How Supplied - Probenecid Tablets, USP are available containing 500 mg of Probenecid, USP. - The tablets are capsule shaped, film-coated yellow, debossed LCI on one side and 1367 on the other side. They are available as follows: NDC 10135-541-10 bottles of 1000 tablets - NDC 10135-541-10 bottles of 1000 tablets ## Storage Store at 20˚ to 25˚c (68˚-77˚f). Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Probenecid Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Probenecid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Benemid - Probalan # Look-Alike Drug Names There is limited information regarding Probenecid Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Benemid
b0eb655ae1d958de80577d8d7256bee8bc3a9039	wikidoc	Benfluorex	Benfluorex # Overview Benfluorex is an anorectic and hypolipidemic agent that is structurally related to fenfluramine patented and manufactured by a French pharmaceutical company Servier. Two clinical studies have shown it may improve glycemic control and decrease insulin resistance in people with poorly controlled type 2 diabetes. However, Servier is suspected of having marketed Mediator (benfluorex) at odds with the drug's medical properties. # Drug withdrawn On 18 December 2009, the European Medicines Agency (EMEA) recommended the withdrawal of all medicines containing benfluorex in the European Union, because their risks, particularly the risk of heart valve disease (fenfluramine-like cardiovascular side-effects), are greater than their benefits. Thus Frachon et al. showed a significantly higher prevalence of unexplained valvular heart disease in patients taking benfluorex compared to controls. and Weill et al. looked at over 1 million diabetic patients demonstrating a higher hospitalization rate in benfluorex takers for valvular heart disease. In France the medication had been marketed as by Servier as an adjuvant antidiabetic under the name Mediator. The drug was on the market between 1976 and 2009 and is thought to have caused between 500 – 2,000 deaths. The drug was also used in Spain (trade name, Modulator), Portugal and Cyprus. Fenfluramine, a related drug, had been withdrawn from the market in 1997 after reports of heart valve disease, pulmonary hypertension, and development of cardiac fibrosis. This side effect is mediated by the metabolite norfenfluramine on 5HT2B receptors of heart valves (Rothman et al., Circulation 2000), leading to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the tricuspid valve. Both fenfluramine and benfluorex form norfenfluramine as a metabolite. This side effect led to the withdrawal of fenfluramine as an anorectic drug worldwide, and later to the withdrawal of benfluorex in Europe.	Benfluorex Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Benfluorex is an anorectic and hypolipidemic agent that is structurally related to fenfluramine patented and manufactured by a French pharmaceutical company Servier. Two clinical studies have shown it may improve glycemic control and decrease insulin resistance in people with poorly controlled type 2 diabetes.[1][2] However, Servier is suspected of having marketed Mediator (benfluorex) at odds with the drug's medical properties.[3] # Drug withdrawn On 18 December 2009, the European Medicines Agency (EMEA) recommended the withdrawal of all medicines containing benfluorex in the European Union, because their risks, particularly the risk of heart valve disease (fenfluramine-like cardiovascular side-effects), are greater than their benefits.[4] Thus Frachon et al. showed a significantly higher prevalence of unexplained valvular heart disease in patients taking benfluorex compared to controls.[5] and Weill et al. looked at over 1 million diabetic patients demonstrating a higher hospitalization rate in benfluorex takers for valvular heart disease.[6] In France the medication had been marketed as by Servier as an adjuvant antidiabetic under the name Mediator. The drug was on the market between 1976 and 2009 and is thought to have caused between 500 – 2,000 deaths.[7] The drug was also used in Spain (trade name, Modulator), Portugal and Cyprus. Fenfluramine, a related drug, had been withdrawn from the market in 1997 after reports of heart valve disease,[8][9] pulmonary hypertension, and development of cardiac fibrosis. This side effect is mediated by the metabolite norfenfluramine on 5HT2B receptors of heart valves (Rothman et al., Circulation 2000), leading to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the tricuspid valve. Both fenfluramine and benfluorex form norfenfluramine as a metabolite. This side effect led to the withdrawal of fenfluramine as an anorectic drug worldwide, and later to the withdrawal of benfluorex in Europe.	https://www.wikidoc.org/index.php/Benfluorex
e09d3cdfc2a8630aee7f49be0e4891376ce1e383	wikidoc	Olmesartan	Olmesartan # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Olmesartan is an Angiotensin 2 Receptor Blocker that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension，dizziness，headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information - Dosage must be individualized. - Recommended starting dosage: 20 mg PO qd‘’‘ when used as monotherapy in patients who are not volume-contracted. - For patients requiring further reduction in blood pressure after 2 weeks of therapy - Dosage: 40 mg PO qd. Doses above 40 mg do not appear to have greater effect. - Twice-daily dosing offers no advantage over the same total dose given once daily. - No initial dosage adjustment is recommended for elderly patients. - For patients with moderate to marked renal impairment (creatinine clearance <40 mL/min) or with moderate to marked hepatic dysfunction. - For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate Olmesartan under close medical supervision and give consideration to use of a lower starting dose. - Olmesartan may be administered with or without food. - If blood pressure is not controlled by Olmesartan alone, a diuretic may be added. Olmesartan may be administered with other antihypertensive agents. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Olmesartan in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Olmesartan in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Hypertension - Dosing information - Dosage must be individualized. - For children who can swallow tablets - For patients who weigh 20 to <35 kg (44 to 77 lb) - Recommended starting dosage: 10 mg PO qd - For patients who weigh ≥35 kg - Recommended starting dosage: 20 mg PO qd . - For patients requiring further reduction in blood pressure after 2 weeks of therapy - For patients who weigh <35 kg - Maximum dosage: 20 mg PO qd’‘’ - For patients who weigh ≥35 kg - Maximum dosage: 40 mg PO qd’‘’ - Children <1 year of age must not receive Olmesartan for hypertension. - For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below. Follow the suspension preparation instructions below to administer Olmesartan as a suspension. ### Preparation of Suspension (for 200 mL of a 2 mg/mL suspension) - Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty Olmesartan 20 mg tablets and allow to stand for a minimum of 5 minutes. Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute. Repeat 1-minute shaking and 1-minute standing for four additional times. Add 100 mL of Ora-Sweet®- and 50 mL of Ora-Plus®- to the suspension and shake well for at least 1 minute. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension well before each use and return promptly to the refrigerator. - Ora-Sweet® and Ora-Plus® are registered trademarks of Paddock Laboratories, Inc. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Olmesartan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Olmesartan in pediatric patients. # Contraindications Do not co-administer aliskiren with Olmesartan in patients with diabetes. # Warnings ## Fetal Toxicity ## Pregnancy Category D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Olmesartan as soon as possible. ## Morbidity in Infants - Children <1 year of age must not receive Olmesartan for hypertension. Drugs that act directly on the renin-angiotensin aldosterone system (RAAS) can have effects on the development of immature kidneys. ## Hypotension in Volume- or Salt-Depleted Patients - In patients with an activated renin-angiotensin aldosterone system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with Olmesartan. Initiate treatment under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. ## Impaired Renal Function - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with Olmesartan. In patients whose renal function may depend upon the activity of the renin angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with Olmesartan. - In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of Olmesartan in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected. ## Sprue-like Enteropathy - Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Olmesartan in cases where no other etiology is identified. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. ### Adult Hypertension - Olmesartan has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Treatment with Olmesartan was well tolerated, with an incidence of adverse reactions similar to placebo. Events generally were mild, transient and had no relationship to the dose of Olmesartan. - The overall frequency of adverse reactions was not dose-related. Analysis of gender, age and race groups demonstrated no differences between Olmesartan and placebo-treated patients. The rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with Olmesartan and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated with Olmesartan and at a higher incidence versus placebo was dizziness (3% vs. 1%). - The following adverse reactions occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with Olmesartan, but also occurred at about the same or greater incidence in patients receiving placebo: back pain, bronchitis, increased creatine phosphokinase , diarrhea, headache, hematuria, hyperglycemia, hypertriglyceridemia, influenza-like symptoms, pharyngitis, rhinitis and sinusitis. - The incidence of cough was similar in placebo (0.7%) and Olmesartan (0.9%) patients. - Other potentially important adverse reactions that have been reported with an incidence of greater than 0.5%, whether or not attributed to treatment, in the more than 3100 hypertensive patients treated with Olmesartan monotherapy in controlled or open-label trials are listed below. Body as a Whole: chest pain, peripheral edema Central and Peripheral Nervous System: vertigo Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, nausea Heart Rate and Rhythm Disorders: tachycardia Metabolic and Nutritional Disorders: hypercholesterolemia, hyperlipemia, hyperuricemia Musculoskeletal: arthralgia, arthritis, myalgia Skin and Appendages: rash - Facial edema was reported in five patients receiving Olmesartan. Angioedema has been reported with angiotensin II antagonists. Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Olmesartan. Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g/dL and 0.3 volume percent, respectively) were observed. Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin were observed infrequently. Five patients (0.1%) assigned to Olmesartan and one patient (0.2%) assigned to placebo in clinical trials were withdrawn because of abnormal liver chemistries (transaminases or total bilirubin). Of the five Olmesartan patients, three had elevated transaminases, which were attributed to alcohol use, and one had a single elevated bilirubin value, which normalized while treatment continued. ### Pediatric Hypertension - No relevant differences were identified between the adverse experience profile for pediatric patients aged 1 to16 years and that previously reported for adult patients. ## Postmarketing Experience The following adverse reactions have been reported in post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Asthenia, angioedema, anaphylactic reactions Gastrointestinal: Vomiting, sprue-like enteropathy Metabolic and Nutritional Disorders: Hyperkalemia Musculoskeletal: Rhabdomyolysis Urogenital System: Acute renal failure, increased blood creatinine levels Skin and Appendages: Alopecia, pruritus, urticaria # Drug Interactions - No significant drug interactions were reported in studies in which Olmesartan was co-administered with digoxin or warfarin in healthy volunteers. - The bioavailability of olmesartan was not significantly altered by the co-administration of antacids . - Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected. ## Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy. - The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors. ## Dual Blockade of the Renin-Angiotensin System (RAS) - Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Olmesartan and other agents that affect the RAS. - Do not co-administer aliskiren with Olmesartan in patients with diabetes. Avoid use of aliskiren with Olmesartan in patients with renal impairment (GFR <60 ml/min). ## Colesevelam hydrochloride - Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Olmesartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramniosis observed, discontinue Olmesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Olmesartan for hypotension, oliguria , and hyperkalemia . Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Olmesartan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Olmesartan during labor and delivery. ### Nursing Mothers - It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Neonates with a history of in utero exposure to Olmesartan: - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. - The antihypertensive effects of Olmesartan were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age. The pharmacokinetics of Olmesartan were evaluated in pediatric patients 1 to 16 years of age. Olmesartan was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults. - Olmesartan has not been shown to be effective for hypertensionin children <6 years of age. - Children <1 year of age must not receive Olmesartan for hypertension . The renin-angiotensin aldosterone system (RAAS) plays a critical role in kidney development. RAAS blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the renin- angiotensin aldosterone system (RAAS) can alter normal renal development. ### Geriatic Use - Of the total number of hypertensive patients receiving Olmesartan in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Olmesartan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Olmesartan with respect to specific racial populations. ### Renal Impairment - Patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). ### Hepatic Impairment - Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. No initial dosage adjustment is recommended for patients with moderate to marked hepatic dysfunction. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Olmesartan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Olmesartan in patients who are immunocompromised. ### Black patient - The antihypertensive effect of Olmesartan was smaller in black patients (usually a low renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for Olmesartan contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotensionoccurs, initiate supportive treatment. The dialyzability of olmesartan is unknown. # Pharmacology ## Mechanism of Action There is limited information regarding Olmesartan Mechanism of Action in the drug label. ## Structure - Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist. - Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4-(1 hydroxy-1-methylethyl)-2-propyl-1-imidazole-5 carboxylate, cyclic 2,3-carbonate. - Its empirical formula is C29H30N6O6 and its structural formula is: ## Pharmacodynamics - Olmesartan doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of Olmesartan >40 mg giving >90% inhibition at 24 hours. - Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of Olmesartan to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg Olmesartan had minimal influence on aldosterone levels and no effect on serum potassium. ## Pharmacokinetics ### Absorption - Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. - Olmesartan tablets and the suspension formulation prepared from Olmesartan tablets are bioequivalent. - The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan. ### Distribution - The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses. - In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats. ### Metabolism and Excretion - Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile. - Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing. ### Geriatric - The pharmacokinetics of olmesartan were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR. ### Pediatric - The pharmacokinetics of olmesartan were studied in pediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in pediatric patients was similar to that in adult patients when adjusted by the body weight. - Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age. ### Gender - Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and Cmax were 10-15% higher in women than in men. ### Hepatic Insufficiency - Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. ### Renal Insufficiency - In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil. - Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested). - Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating. ## Animal Toxicology and/or Pharmacology ### Reproductive Toxicology Studies - No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose of olmesartan medoxomil on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day. # Clinical Studies ## Adult Hypertension - The antihypertensive effects of Olmesartan have been demonstrated in seven placebo controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure. A total of 2693 patients (2145 Olmesartan; 548 placebo) with essential hypertensionwere studied. Olmesartan once daily lowered diastolic and systolic blood pressure. The response was dose-related, as shown in the following graph. A Olmesartan dose of 20 mg daily produces a trough sitting BP reduction over placebo of about 10/6 mmHg and a dose of 40 mg daily produces a trough sitting BP reduction over placebo of about 12/7 mmHg. Olmesartan doses greater than 40 mg had little additional effect. The onset of the antihypertensive effect occurred within 1 week and was largely manifest after 2 weeks. - Data above are from seven placebo-controlled studies (2145 Olmesartan patients, 548 placebo patients). The blood pressure lowering effect was maintained throughout the 24-hour period with Olmesartan once daily, with trough-to-peak ratios for systolic and diastolic response between 60 and 80%. - The blood pressure lowering effect of Olmesartan, with and without hydrochlorothiazide, was maintained in patients treated for up to 1 year. There was no evidence of tachyphylaxisduring long-term treatment with Olmesartan or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1 year of treatment. - The antihypertensive effect of Olmesartan was similar in men and women and in patients older and younger than 65 years. The effect was smaller in black patients (usually a low renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers. Olmesartan had an additional blood pressure lowering effect when added to hydrochlorothiazide. - There are no trials of Olmesartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits. ## Pediatric Hypertension - The antihypertensive effects of Olmesartan in the pediatric population were evaluated in a randomized, double-blind study involving 302 hypertensive patients aged 6 to 16 years. The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The etiology of the hypertensionwas predominantly essential hypertension(87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 or 20 mg of Olmesartan once daily and patients who weighed ≥35 kg were randomized to 5 or 40 mg of Olmesartan once daily. At the end of 3 weeks, patients were re-randomized to continuing Olmesartan or to taking placebo for up to 2 weeks. During the initial dose-response phase, Olmesartan significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Overall, the two dose levels of Olmesartan (low and high) significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively. These reductions in systolic blood pressure included both drug and placebo effect. During the randomized withdrawal to placebo phase, mean systolic blood pressure at trough was 3.2 mmHg lower and mean diastolic blood pressure at trough was 2.8 mmHg lower in patients continuing Olmesartan than in patients withdrawn to placebo. These differences were statistically different. As observed in adult populations, the blood pressure reductions were smaller in black patients. - In the same study, 59 patients aged 1 to 5 years who weighed ≥5 kg received 0.3 mg/kg of Olmesartan once daily for three weeks in an open label phase and then were randomized to receiving Olmesartan or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to Olmesartan; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7). # How Supplied - Olmesartan is supplied as yellow, round, film-coated, non-scored tablets containing 5 mg of olmesartan medoxomil, as white, round, film-coated, non-scored tablets containing 20 mg of olmesartan medoxomil, and as white, oval-shaped, film-coated, non-scored tablets containing 40 mg of olmesartan medoxomil. Tablets are debossed with Sankyo on one side and C12, C14, or C15 on the other side of the 5, 20, and 40 mg tablets, respectively. Tablets are supplied as follows: ## Storage - Store at 20-25°C (68-77°F) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Olmesartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. # Precautions with Alcohol Of the five Olmesartan patients, three had elevated transaminases, which were attributed to alcohol use, and one had a single elevated bilirubin value, which normalized while treatment continued. # Brand Names - Benicar ® # Look-Alike Drug Names Olmesartan - Mevacor # Drug Shortage Status # Price	Olmesartan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2], Rabin Bista, M.B.B.S. [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Olmesartan is an Angiotensin 2 Receptor Blocker that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension，dizziness，headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information - Dosage must be individualized. - Recommended starting dosage: 20 mg PO qd‘’‘ when used as monotherapy in patients who are not volume-contracted. - For patients requiring further reduction in blood pressure after 2 weeks of therapy - Dosage: 40 mg PO qd. Doses above 40 mg do not appear to have greater effect. - Twice-daily dosing offers no advantage over the same total dose given once daily. - No initial dosage adjustment is recommended for elderly patients. - For patients with moderate to marked renal impairment (creatinine clearance <40 mL/min) or with moderate to marked hepatic dysfunction. - For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate Olmesartan under close medical supervision and give consideration to use of a lower starting dose. - Olmesartan may be administered with or without food. - If blood pressure is not controlled by Olmesartan alone, a diuretic may be added. Olmesartan may be administered with other antihypertensive agents. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Olmesartan in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Olmesartan in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Hypertension - Dosing information - Dosage must be individualized. - For children who can swallow tablets - For patients who weigh 20 to <35 kg (44 to 77 lb) - Recommended starting dosage: 10 mg PO qd - For patients who weigh ≥35 kg - Recommended starting dosage: 20 mg PO qd . - For patients requiring further reduction in blood pressure after 2 weeks of therapy - For patients who weigh <35 kg - Maximum dosage: 20 mg PO qd’‘’ - For patients who weigh ≥35 kg - Maximum dosage: 40 mg PO qd’‘’ - Children <1 year of age must not receive Olmesartan for hypertension. - For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below. Follow the suspension preparation instructions below to administer Olmesartan as a suspension. ### Preparation of Suspension (for 200 mL of a 2 mg/mL suspension) - Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty Olmesartan 20 mg tablets and allow to stand for a minimum of 5 minutes. Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute. Repeat 1-minute shaking and 1-minute standing for four additional times. Add 100 mL of Ora-Sweet®* and 50 mL of Ora-Plus®* to the suspension and shake well for at least 1 minute. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension well before each use and return promptly to the refrigerator. - Ora-Sweet® and Ora-Plus® are registered trademarks of Paddock Laboratories, Inc. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Olmesartan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Olmesartan in pediatric patients. # Contraindications Do not co-administer aliskiren with Olmesartan in patients with diabetes. # Warnings ## Fetal Toxicity ## Pregnancy Category D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Olmesartan as soon as possible. ## Morbidity in Infants - Children <1 year of age must not receive Olmesartan for hypertension. Drugs that act directly on the renin-angiotensin aldosterone system (RAAS) can have effects on the development of immature kidneys. ## Hypotension in Volume- or Salt-Depleted Patients - In patients with an activated renin-angiotensin aldosterone system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with Olmesartan. Initiate treatment under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. ## Impaired Renal Function - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with Olmesartan. In patients whose renal function may depend upon the activity of the renin angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with Olmesartan. - In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of Olmesartan in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected. ## Sprue-like Enteropathy - Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Olmesartan in cases where no other etiology is identified. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. ### Adult Hypertension - Olmesartan has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Treatment with Olmesartan was well tolerated, with an incidence of adverse reactions similar to placebo. Events generally were mild, transient and had no relationship to the dose of Olmesartan. - The overall frequency of adverse reactions was not dose-related. Analysis of gender, age and race groups demonstrated no differences between Olmesartan and placebo-treated patients. The rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with Olmesartan and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated with Olmesartan and at a higher incidence versus placebo was dizziness (3% vs. 1%). - The following adverse reactions occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with Olmesartan, but also occurred at about the same or greater incidence in patients receiving placebo: back pain, bronchitis, increased creatine phosphokinase , diarrhea, headache, hematuria, hyperglycemia, hypertriglyceridemia, influenza-like symptoms, pharyngitis, rhinitis and sinusitis. - The incidence of cough was similar in placebo (0.7%) and Olmesartan (0.9%) patients. - Other potentially important adverse reactions that have been reported with an incidence of greater than 0.5%, whether or not attributed to treatment, in the more than 3100 hypertensive patients treated with Olmesartan monotherapy in controlled or open-label trials are listed below. Body as a Whole: chest pain, peripheral edema Central and Peripheral Nervous System: vertigo Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, nausea Heart Rate and Rhythm Disorders: tachycardia Metabolic and Nutritional Disorders: hypercholesterolemia, hyperlipemia, hyperuricemia Musculoskeletal: arthralgia, arthritis, myalgia Skin and Appendages: rash - Facial edema was reported in five patients receiving Olmesartan. Angioedema has been reported with angiotensin II antagonists. Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Olmesartan. Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g/dL and 0.3 volume percent, respectively) were observed. Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin were observed infrequently. Five patients (0.1%) assigned to Olmesartan and one patient (0.2%) assigned to placebo in clinical trials were withdrawn because of abnormal liver chemistries (transaminases or total bilirubin). Of the five Olmesartan patients, three had elevated transaminases, which were attributed to alcohol use, and one had a single elevated bilirubin value, which normalized while treatment continued. ### Pediatric Hypertension - No relevant differences were identified between the adverse experience profile for pediatric patients aged 1 to16 years and that previously reported for adult patients. ## Postmarketing Experience The following adverse reactions have been reported in post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Asthenia, angioedema, anaphylactic reactions Gastrointestinal: Vomiting, sprue-like enteropathy Metabolic and Nutritional Disorders: Hyperkalemia Musculoskeletal: Rhabdomyolysis Urogenital System: Acute renal failure, increased blood creatinine levels Skin and Appendages: Alopecia, pruritus, urticaria # Drug Interactions - No significant drug interactions were reported in studies in which Olmesartan was co-administered with digoxin or warfarin in healthy volunteers. - The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2]. - Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected. ## Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) - In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy. - The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors. ## Dual Blockade of the Renin-Angiotensin System (RAS) - Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Olmesartan and other agents that affect the RAS. - Do not co-administer aliskiren with Olmesartan in patients with diabetes. Avoid use of aliskiren with Olmesartan in patients with renal impairment (GFR <60 ml/min). ## Colesevelam hydrochloride - Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Olmesartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramniosis observed, discontinue Olmesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Olmesartan for hypotension, oliguria , and hyperkalemia . Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Olmesartan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Olmesartan during labor and delivery. ### Nursing Mothers - It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Neonates with a history of in utero exposure to Olmesartan: - If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. - The antihypertensive effects of Olmesartan were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age. The pharmacokinetics of Olmesartan were evaluated in pediatric patients 1 to 16 years of age. Olmesartan was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults. - Olmesartan has not been shown to be effective for hypertensionin children <6 years of age. - Children <1 year of age must not receive Olmesartan for hypertension . The renin-angiotensin aldosterone system (RAAS) plays a critical role in kidney development. RAAS blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the renin- angiotensin aldosterone system (RAAS) can alter normal renal development. ### Geriatic Use - Of the total number of hypertensive patients receiving Olmesartan in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender There is no FDA guidance on the use of Olmesartan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Olmesartan with respect to specific racial populations. ### Renal Impairment - Patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). ### Hepatic Impairment - Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. No initial dosage adjustment is recommended for patients with moderate to marked hepatic dysfunction. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Olmesartan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Olmesartan in patients who are immunocompromised. ### Black patient - The antihypertensive effect of Olmesartan was smaller in black patients (usually a low renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for Olmesartan contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage - Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotensionoccurs, initiate supportive treatment. The dialyzability of olmesartan is unknown. # Pharmacology ## Mechanism of Action There is limited information regarding Olmesartan Mechanism of Action in the drug label. ## Structure - Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist. - Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4-(1 hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5 carboxylate, cyclic 2,3-carbonate. - Its empirical formula is C29H30N6O6 and its structural formula is: ## Pharmacodynamics - Olmesartan doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of Olmesartan >40 mg giving >90% inhibition at 24 hours. - Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of Olmesartan to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg Olmesartan had minimal influence on aldosterone levels and no effect on serum potassium. ## Pharmacokinetics ### Absorption - Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. - Olmesartan tablets and the suspension formulation prepared from Olmesartan tablets are bioequivalent. - The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan. ### Distribution - The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses. - In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats. ### Metabolism and Excretion - Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile. - Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing. ### Geriatric - The pharmacokinetics of olmesartan were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR. ### Pediatric - The pharmacokinetics of olmesartan were studied in pediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in pediatric patients was similar to that in adult patients when adjusted by the body weight. - Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age. ### Gender - Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and Cmax were 10-15% higher in women than in men. ### Hepatic Insufficiency - Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. ### Renal Insufficiency - In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil. - Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested). - Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating. ## Animal Toxicology and/or Pharmacology ### Reproductive Toxicology Studies - No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose [MRHD] of olmesartan medoxomil on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day. # Clinical Studies ## Adult Hypertension - The antihypertensive effects of Olmesartan have been demonstrated in seven placebo controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure. A total of 2693 patients (2145 Olmesartan; 548 placebo) with essential hypertensionwere studied. Olmesartan once daily lowered diastolic and systolic blood pressure. The response was dose-related, as shown in the following graph. A Olmesartan dose of 20 mg daily produces a trough sitting BP reduction over placebo of about 10/6 mmHg and a dose of 40 mg daily produces a trough sitting BP reduction over placebo of about 12/7 mmHg. Olmesartan doses greater than 40 mg had little additional effect. The onset of the antihypertensive effect occurred within 1 week and was largely manifest after 2 weeks. - Data above are from seven placebo-controlled studies (2145 Olmesartan patients, 548 placebo patients). The blood pressure lowering effect was maintained throughout the 24-hour period with Olmesartan once daily, with trough-to-peak ratios for systolic and diastolic response between 60 and 80%. - The blood pressure lowering effect of Olmesartan, with and without hydrochlorothiazide, was maintained in patients treated for up to 1 year. There was no evidence of tachyphylaxisduring long-term treatment with Olmesartan or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1 year of treatment. - The antihypertensive effect of Olmesartan was similar in men and women and in patients older and younger than 65 years. The effect was smaller in black patients (usually a low renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers. Olmesartan had an additional blood pressure lowering effect when added to hydrochlorothiazide. - There are no trials of Olmesartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits. ## Pediatric Hypertension - The antihypertensive effects of Olmesartan in the pediatric population were evaluated in a randomized, double-blind study involving 302 hypertensive patients aged 6 to 16 years. The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The etiology of the hypertensionwas predominantly essential hypertension(87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 or 20 mg of Olmesartan once daily and patients who weighed ≥35 kg were randomized to 5 or 40 mg of Olmesartan once daily. At the end of 3 weeks, patients were re-randomized to continuing Olmesartan or to taking placebo for up to 2 weeks. During the initial dose-response phase, Olmesartan significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Overall, the two dose levels of Olmesartan (low and high) significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively. These reductions in systolic blood pressure included both drug and placebo effect. During the randomized withdrawal to placebo phase, mean systolic blood pressure at trough was 3.2 mmHg lower and mean diastolic blood pressure at trough was 2.8 mmHg lower in patients continuing Olmesartan than in patients withdrawn to placebo. These differences were statistically different. As observed in adult populations, the blood pressure reductions were smaller in black patients. - In the same study, 59 patients aged 1 to 5 years who weighed ≥5 kg received 0.3 mg/kg of Olmesartan once daily for three weeks in an open label phase and then were randomized to receiving Olmesartan or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to Olmesartan; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7). # How Supplied - Olmesartan is supplied as yellow, round, film-coated, non-scored tablets containing 5 mg of olmesartan medoxomil, as white, round, film-coated, non-scored tablets containing 20 mg of olmesartan medoxomil, and as white, oval-shaped, film-coated, non-scored tablets containing 40 mg of olmesartan medoxomil. Tablets are debossed with Sankyo on one side and C12, C14, or C15 on the other side of the 5, 20, and 40 mg tablets, respectively. Tablets are supplied as follows: ## Storage - Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Olmesartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. # Precautions with Alcohol Of the five Olmesartan patients, three had elevated transaminases, which were attributed to alcohol use, and one had a single elevated bilirubin value, which normalized while treatment continued. # Brand Names - Benicar ®[1] # Look-Alike Drug Names Olmesartan - Mevacor[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Benicar
168c6489180288c26227634a031a1d02a30b0ec8	wikidoc	Benzamycin	Benzamycin Benzamycin is topical gel composed of 5% benzoyl peroxide and 3% erythromycin. Developed and manufactured by Dermik Laboratories, its main usage is to fight acne. Benzamycin is a prescription medication. Side effects include dry skin, stinging, redness, and itchy rash (urticaria). Recommended usage is 2 times per day, once in the morning and once in the evening, or as prescribed by your doctor. The affected area should be washed with soap and warm water, rinsed, and gently dried before applying the gel. Using an oil-free face moisturizer in conjunction with Benzamycin is recommended. On March 30, 2004 a generic form of Benzamycin was released by pharmaceutical company Atrix Laboratories. Article on Biospace.com regarding generic Benzamycin In the UK, Benzamycin is made by Schwarz Pharma. Production of Benzamycin has now stopped, for a predicted six months, whilst Schwarz Pharma look for an alternative manufacturer.	Benzamycin Benzamycin is topical gel composed of 5% benzoyl peroxide and 3% erythromycin. Developed and manufactured by Dermik Laboratories, its main usage is to fight acne. Benzamycin is a prescription medication. Side effects include dry skin, stinging, redness, and itchy rash (urticaria). Recommended usage is 2 times per day, once in the morning and once in the evening, or as prescribed by your doctor. The affected area should be washed with soap and warm water, rinsed, and gently dried before applying the gel. Using an oil-free face moisturizer in conjunction with Benzamycin is recommended. On March 30, 2004 a generic form of Benzamycin was released by pharmaceutical company Atrix Laboratories. Article on Biospace.com regarding generic Benzamycin In the UK, Benzamycin is made by Schwarz Pharma. Production of Benzamycin has now stopped, for a predicted six months, whilst Schwarz Pharma look for an alternative manufacturer. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Benzamycin
6c1c8bfbd6a493f773486c4ba16d866d80193037	wikidoc	Penicillin	Penicillin # Overview Penicillin (sometimes abbreviated PCN) refers to a group of beta-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. The name “penicillin” can also be used in reference to a specific member of the penicillin group Penam Skeleton, which has the molecular formula R-C9H11N2O4S, where R is a variable side chain. # History The discovery of penicillin is usually attributed to Scottish scientist Sir Alexander Fleming in 1928, though others had earlier noted the antibacterial effects of Penicillium. The development of penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey. In March 2000, doctors of the San Juan de Dios Hospital in San Jose (Costa Rica) published manuscripts belonging to the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (1887-1944). The manuscripts explained Picado's experiences between 1915 and 1927 about the inhibitory actions of the fungi of genera Penic. Apparently Clorito Picado had reported his discovery to the Paris Academy of Sciences in Paris, yet did not patent it, even though his investigation had started years before Fleming's. Fleming, at his laboratory in St. Mary's Hospital (now one of Imperial College's teaching hospitals) in London, noticed a halo of inhibition of bacterial growth around a contaminant blue-green mold Staphylococcus plate culture. Fleming concluded that the mold was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture of the mold and discovered that it was a Penicillium mold, now known to be Penicillium notatum. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the Penicillium mold. Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, but particularly noted its laboratory value in the isolation of "Bacillus influenzae" (now Haemophilus influenzae). After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria and stopped studying penicillin after 1931, but restarted some clinical trials in 1934 and continued to try to get someone to purify it until 1940. . In 1939, Australian scientist Howard Walter Florey and a team of researchers (Ernst Boris Chain, A. D. Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the in vivo bactericidal action of penicillin. Their attempts to treat humans failed due to insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander), but they proved its harmlessness and effect on mice. A mouldy cantaloupe in a Peoria market in 1941 was found to contain the best and highest quality penicillin after a world-wide search. Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford. On March 3, 1942 John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin. During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds amongst Allied forces; saving an estimated 12-15% of lives. Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug necessitating frequent dosing. Penicillins are actively secreted and about 80% of a penicillin dose is cleared within three to four hours of administration. During those times it became common procedure to collect the urine from patients being treated so that the penicillin could be isolated and reused. This was not a satisfactory solution, however, so researchers looked for a way to slow penicillin secretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for secretion such that the transporter would preferentially secrete the competitive inhibitor. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are concomitantly administered, probenecid competitively inhibits the secretion of penicillin, increasing its concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined.Probenecid is still clinically useful, however, for certain infections requiring particularly high concentrations of penicillins. The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in the early 1940s. A team of Oxford research scientists led by Australian Howard Walter Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass producing the drug. Chemist John Sheehan at MIT completed the first total synthesis of penicillin and some of its analogs in the early 1950s, but his methods were not efficient for mass production. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for this work. Penicillin has since become the most widely used antibiotic to date and is still used for many Gram-positive bacterial infections. # Developments from penicillin The narrow spectrum of activity of the penicillins, along with the poor activity of the orally-active phenoxymethylpenicillin, led to the search for derivatives of penicillin which could treat a wider range of infections. The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins. Further development yielded beta-lactamase-resistant penicillins including flucloxacillin, dicloxacillin and methicillin. These were significant for their activity against beta-lactamase-producing bacteria species, but are ineffective against the methicillin-resistant Staphylococcus aureus strains that subsequently emerged. The line of true penicillins were the antipseudomonal penicillins, such as ticarcillin and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the beta-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most importantly, the cephalosporins, have this at the centre of their structures. # Mechanism of action β-lactam antibiotics work by inhibiting the formation of peptidoglycan cross-links in the bacterial cell wall. The β-lactam moiety (functional group) of penicillin binds to the enzyme (DD-transpeptidase) that links the peptidoglycan molecules in bacteria, and this weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis or death). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and auto lysins which further digest the bacteria's existing peptidoglycan. When the bacteria lose their cell walls they are then called spheroplasts. Penicillin shows a synergistic effect with aminoglycosides since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing its disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms. # Variants in clinical use The term “penicillin” is often used generically to refer to one of the narrow-spectrum penicillins, particularly benzylpenicillin. ## Benzathine benzylpenicillin Benzathine benzylpenicillin (rINN), also known as benzathine penicillin, is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo. It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose. It is marketed by Wyeth under the trade name Bicillin L-A. Specific indications for benzathine pencillin include: - Prophylaxis of rheumatic fever - Early or latent syphilis ## Benzylpenicillin (penicillin G) Benzylpenicillin, commonly known as penicillin G, is the gold standard penicillin. Penicillin G is typically given by a parenteral route of administration (not orally) because it is unstable in the hydrochloric acid of the stomach. Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity. Specific indications for benzylpenicillin include: - Cellulitis - Bacterial endocarditis - Gonorrhea - Meningitis - Aspiration pneumonia, lung abscess - Community-acquired pneumonia - Syphilis - Septicaemia in children ## Phenoxymethylpenicillin (penicillin V) Phenoxymethylpenicillin, commonly known as penicillin V, is the orally-active form of penicillin. It is less active than benzylpenicillin, however, and is only appropriate in conditions where high tissue concentrations are not required. Specific indications for phenoxymethylpenicillin include: - Infections caused by Streptococcus pyogenes Tonsillitis Pharyngitis Skin infections - Tonsillitis - Pharyngitis - Skin infections - Prophylaxis of rheumatic fever - Moderate-to-severe gingivitis (with metronidazole) Penicillin V is the first choice in the treatment of odontogenic infections. ## Procaine benzylpenicillin Procaine benzylpenicillin (rINN), also known as procaine penicillin, is a combination of benzylpenicillin with the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin — thus it is used where prolonged low concentrations of benzylpenicillin are required. This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin. It is widely used in veterinary settings. Specific indications for procaine penicillin include: - Syphilis It should be noted that in the United States, Bicillin C-R (a injectable suspension which 1.2 million units of benzathine penicillin & 1.2 million units of procaine penicillin per 4 mL) is not recommended for treating syphilis, since it contains only half the recommended dose of benzathine penicillin. Medication errors have been made due to the confusion between Bicillin L-A & Bicillin C-R. As a result, changes in product packaging have been made; specifically, the statement "Not for the Treatment of Syphilis" has been added in red text to both the Bicillin CR and Billin CR 900/300 syringe labels. - It should be noted that in the United States, Bicillin C-R (a injectable suspension which 1.2 million units of benzathine penicillin & 1.2 million units of procaine penicillin per 4 mL) is not recommended for treating syphilis, since it contains only half the recommended dose of benzathine penicillin. Medication errors have been made due to the confusion between Bicillin L-A & Bicillin C-R. As a result, changes in product packaging have been made; specifically, the statement "Not for the Treatment of Syphilis" has been added in red text to both the Bicillin CR and Billin CR 900/300 syringe labels. - Respiratory tract infections where compliance with oral treatment is unlikely - Cellulitis, erysipelas Procaine penicillin is also used as an adjunct in the treatment of anthrax. # Semi-synthetic penicillins Structural modifications were made to the side chain of the penicillin nucleus in an effort to improve oral bioavailability, improve stability to beta-lactamase activity, and increase the spectrum of action. ## Narrow spectrum penicillinase-resistant penicillins This group was developed to be effective against beta-lactamases produced by Staphylococcus aureus, and are occasionally known as anti-staphylococcal penicillin. Penicillin is rampantly used for curing infections and to prevent growth of harmful mold. - Methicillin discontinued (not used clinically) - Dicloxacillin - Flucloxacillin - Oxacillin - Nafcillin - Cloxacillin ## Narrow spectrum β-lactamase-resistant penicillins This molecule has a spectrum directed towards Gram negative bacteria without activity on Pseudomonas aeruginosa or Acinetobacter spp. with remarkable resistance to any type of β-lactamase. - Temocillin ## Moderate spectrum penicillins This group was developed to increase the spectrum of action and, in the case of amoxicillin, improve oral bioavailability. - Amoxicillin - Ampicillin And the prodrugs of ampicillin that are converted in the body to ampicillin: - Hetacillin, not used now. - Bacampicillin - Pivampicillin ## Extended Spectrum Penicillins This group was developed to increase efficacy against Gram-negative organisms. Some members of this group also display activity against Pseudomonas aeruginosa. - Piperacillin - Ticarcillin - Azlocillin - Carbenicillin - Mezlocillin ## Penicillins with beta-lactamase inhibitors Penicillins may be combined with beta-lactamase inhibitors to increase efficacy against β-lactamase-producing organisms. The addition of the beta-lactamase inhibitor does not generally, in itself, increase the spectrum of the partner penicillin. - Amoxicillin/clavulanic acid - Ampicillin/sulbactam - Ticarcillin/clavulanic acid - Piperacillin/tazobactam ## Other Penicillins - Metampicillin - Broadcillin - Epicillin - Ampicillin benzathine - Talampicillin - Combipenix - Ampicillinoic acid - N-(N'-Methylasparaginyl)amoxicillin - Aspoxicillin - N-Propionylampicillin - Lenampicillin - Sulacillin # Adverse effects ## Adverse drug reactions Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include: diarrhea, nausea, rash, urticaria, and/or superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include: fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics) and/or pseudomembranous colitis. Pain and inflammation at the injection site is also common for parenterally-administered benzathine benzylpenicillin, benzylpenicillin, and to a lesser extent procaine benzylpenicillin. ## Allergy/hypersensitivity Although penicillin is still the most commonly reported allergy, less than 20% of all patients who believe that they have a penicillin allergy are truly allergic to penicillin; nevertheless, penicillin is still the most common cause of severe allergic drug reactions. Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent. Anaphylaxis will occur in approximately 0.01% of patients. There is about a 5% cross-sensitivity between penicillin-derivatives, cephalosporins and carbapenems. This risk warrants extreme caution with all β-lactam antibiotics in patients with a history of severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic. The PEN-FAST questions can help predict whether a patient has allergies: - F: Fives years or less since an allergy event (2 points) - A: Anaphylaxis/angioedema OR - S: severe cutaneous adverse reaction (2 points) - T: Treatment required for reaction (1 point) Interpretation of the PEN-FAST: 0: Very low risk < 1% 1-2: Low risk - 5%	Penicillin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview Penicillin (sometimes abbreviated PCN) refers to a group of beta-lactam antibiotics used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. The name “penicillin” can also be used in reference to a specific member of the penicillin group Penam Skeleton, which has the molecular formula R-C9H11N2O4S, where R is a variable side chain. # History The discovery of penicillin is usually attributed to Scottish scientist Sir Alexander Fleming in 1928, though others had earlier noted the antibacterial effects of Penicillium. The development of penicillin for use as a medicine is attributed to the Australian Nobel Laureate Howard Walter Florey. In March 2000, doctors of the San Juan de Dios Hospital in San Jose (Costa Rica) published manuscripts belonging to the Costa Rican scientist and medical doctor Clodomiro (Clorito) Picado Twight (1887-1944). The manuscripts explained Picado's experiences between 1915 and 1927 about the inhibitory actions of the fungi of genera Penic. Apparently Clorito Picado had reported his discovery to the Paris Academy of Sciences in Paris, yet did not patent it, even though his investigation had started years before Fleming's. Fleming, at his laboratory in St. Mary's Hospital (now one of Imperial College's teaching hospitals) in London, noticed a halo of inhibition of bacterial growth around a contaminant blue-green mold Staphylococcus plate culture. Fleming concluded that the mold was releasing a substance that was inhibiting bacterial growth and lysing the bacteria. He grew a pure culture of the mold and discovered that it was a Penicillium mold, now known to be Penicillium notatum. Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the Penicillium mold. Even in these early stages, penicillin was found to be most effective against Gram-positive bacteria, and ineffective against Gram-negative organisms and fungi. He expressed initial optimism that penicillin would be a useful disinfectant, being highly potent with minimal toxicity compared to antiseptics of the day, but particularly noted its laboratory value in the isolation of "Bacillus influenzae" (now Haemophilus influenzae).[1] After further experiments, Fleming was convinced that penicillin could not last long enough in the human body to kill pathogenic bacteria and stopped studying penicillin after 1931, but restarted some clinical trials in 1934 and continued to try to get someone to purify it until 1940. .[2] In 1939, Australian scientist Howard Walter Florey and a team of researchers (Ernst Boris Chain, A. D. Gardner, Norman Heatley, M. Jennings, J. Orr-Ewing and G. Sanders) at the Sir William Dunn School of Pathology, University of Oxford made significant progress in showing the in vivo bactericidal action of penicillin. Their attempts to treat humans failed due to insufficient volumes of penicillin (the first patient treated was Reserve Constable Albert Alexander), but they proved its harmlessness and effect on mice. A mouldy cantaloupe in a Peoria market in 1941 was found to contain the best and highest quality penicillin after a world-wide search.[3] Some of the pioneering trials of penicillin took place at the Radcliffe Infirmary in Oxford. On March 3, 1942 John Bumstead and Orvan Hess became the first in the world to successfully treat a patient using penicillin.[4][5] During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds amongst Allied forces; saving an estimated 12-15% of lives. Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug necessitating frequent dosing. Penicillins are actively secreted and about 80% of a penicillin dose is cleared within three to four hours of administration. During those times it became common procedure to collect the urine from patients being treated so that the penicillin could be isolated and reused.[6] This was not a satisfactory solution, however, so researchers looked for a way to slow penicillin secretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for secretion such that the transporter would preferentially secrete the competitive inhibitor. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are concomitantly administered, probenecid competitively inhibits the secretion of penicillin, increasing its concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined.[6]Probenecid is still clinically useful, however, for certain infections requiring particularly high concentrations of penicillins.[7] The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin in the early 1940s. A team of Oxford research scientists led by Australian Howard Walter Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass producing the drug. Chemist John Sheehan at MIT completed the first total synthesis of penicillin and some of its analogs in the early 1950s, but his methods were not efficient for mass production. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for this work. Penicillin has since become the most widely used antibiotic to date and is still used for many Gram-positive bacterial infections. # Developments from penicillin The narrow spectrum of activity of the penicillins, along with the poor activity of the orally-active phenoxymethylpenicillin, led to the search for derivatives of penicillin which could treat a wider range of infections. The first major development was ampicillin, which offered a broader spectrum of activity than either of the original penicillins. Further development yielded beta-lactamase-resistant penicillins including flucloxacillin, dicloxacillin and methicillin. These were significant for their activity against beta-lactamase-producing bacteria species, but are ineffective against the methicillin-resistant Staphylococcus aureus strains that subsequently emerged. The line of true penicillins were the antipseudomonal penicillins, such as ticarcillin and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the beta-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most importantly, the cephalosporins, have this at the centre of their structures. # Mechanism of action β-lactam antibiotics work by inhibiting the formation of peptidoglycan cross-links in the bacterial cell wall. The β-lactam moiety (functional group) of penicillin binds to the enzyme (DD-transpeptidase) that links the peptidoglycan molecules in bacteria, and this weakens the cell wall of the bacterium (in other words, the antibiotic causes cytolysis or death). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and auto lysins which further digest the bacteria's existing peptidoglycan. When the bacteria lose their cell walls they are then called spheroplasts. Penicillin shows a synergistic effect with aminoglycosides since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing its disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms. # Variants in clinical use The term “penicillin” is often used generically to refer to one of the narrow-spectrum penicillins, particularly benzylpenicillin. ## Benzathine benzylpenicillin Benzathine benzylpenicillin (rINN), also known as benzathine penicillin, is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo. It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose. It is marketed by Wyeth under the trade name Bicillin L-A. Specific indications for benzathine pencillin include:[7] - Prophylaxis of rheumatic fever - Early or latent syphilis ## Benzylpenicillin (penicillin G) Benzylpenicillin, commonly known as penicillin G, is the gold standard penicillin. Penicillin G is typically given by a parenteral route of administration (not orally) because it is unstable in the hydrochloric acid of the stomach. Because the drug is given parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity. Specific indications for benzylpenicillin include:[7] - Cellulitis - Bacterial endocarditis - Gonorrhea - Meningitis - Aspiration pneumonia, lung abscess - Community-acquired pneumonia - Syphilis - Septicaemia in children ## Phenoxymethylpenicillin (penicillin V) Phenoxymethylpenicillin, commonly known as penicillin V, is the orally-active form of penicillin. It is less active than benzylpenicillin, however, and is only appropriate in conditions where high tissue concentrations are not required. Specific indications for phenoxymethylpenicillin include:[7] - Infections caused by Streptococcus pyogenes Tonsillitis Pharyngitis Skin infections - Tonsillitis - Pharyngitis - Skin infections - Prophylaxis of rheumatic fever - Moderate-to-severe gingivitis (with metronidazole) Penicillin V is the first choice in the treatment of odontogenic infections. ## Procaine benzylpenicillin Procaine benzylpenicillin (rINN), also known as procaine penicillin, is a combination of benzylpenicillin with the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the circulation and hydrolysed to benzylpenicillin — thus it is used where prolonged low concentrations of benzylpenicillin are required. This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin. It is widely used in veterinary settings. Specific indications for procaine penicillin include:[7] - Syphilis It should be noted that in the United States, Bicillin C-R (a injectable suspension which 1.2 million units of benzathine penicillin & 1.2 million units of procaine penicillin per 4 mL) is not recommended for treating syphilis, since it contains only half the recommended dose of benzathine penicillin. Medication errors have been made due to the confusion between Bicillin L-A & Bicillin C-R.[8] As a result, changes in product packaging have been made; specifically, the statement "Not for the Treatment of Syphilis" has been added in red text to both the Bicillin CR and Billin CR 900/300 syringe labels.[9] - It should be noted that in the United States, Bicillin C-R (a injectable suspension which 1.2 million units of benzathine penicillin & 1.2 million units of procaine penicillin per 4 mL) is not recommended for treating syphilis, since it contains only half the recommended dose of benzathine penicillin. Medication errors have been made due to the confusion between Bicillin L-A & Bicillin C-R.[8] As a result, changes in product packaging have been made; specifically, the statement "Not for the Treatment of Syphilis" has been added in red text to both the Bicillin CR and Billin CR 900/300 syringe labels.[9] - Respiratory tract infections where compliance with oral treatment is unlikely - Cellulitis, erysipelas Procaine penicillin is also used as an adjunct in the treatment of anthrax. # Semi-synthetic penicillins Structural modifications were made to the side chain of the penicillin nucleus in an effort to improve oral bioavailability, improve stability to beta-lactamase activity, and increase the spectrum of action. ## Narrow spectrum penicillinase-resistant penicillins This group was developed to be effective against beta-lactamases produced by Staphylococcus aureus, and are occasionally known as anti-staphylococcal penicillin. Penicillin is rampantly used for curing infections and to prevent growth of harmful mold. - Methicillin discontinued (not used clinically) - Dicloxacillin - Flucloxacillin - Oxacillin - Nafcillin - Cloxacillin ## Narrow spectrum β-lactamase-resistant penicillins This molecule has a spectrum directed towards Gram negative bacteria without activity on Pseudomonas aeruginosa or Acinetobacter spp. with remarkable resistance to any type of β-lactamase. - Temocillin ## Moderate spectrum penicillins This group was developed to increase the spectrum of action and, in the case of amoxicillin, improve oral bioavailability. - Amoxicillin - Ampicillin And the prodrugs of ampicillin that are converted in the body to ampicillin: - Hetacillin, not used now. - Bacampicillin - Pivampicillin ## Extended Spectrum Penicillins This group was developed to increase efficacy against Gram-negative organisms. Some members of this group also display activity against Pseudomonas aeruginosa. - Piperacillin - Ticarcillin - Azlocillin - Carbenicillin - Mezlocillin ## Penicillins with beta-lactamase inhibitors Penicillins may be combined with beta-lactamase inhibitors to increase efficacy against β-lactamase-producing organisms. The addition of the beta-lactamase inhibitor does not generally, in itself, increase the spectrum of the partner penicillin. - Amoxicillin/clavulanic acid - Ampicillin/sulbactam - Ticarcillin/clavulanic acid - Piperacillin/tazobactam ## Other Penicillins - Metampicillin - Broadcillin - Epicillin - Ampicillin benzathine - Talampicillin - Combipenix - Ampicillinoic acid - N-(N'-Methylasparaginyl)amoxicillin - Aspoxicillin - N-Propionylampicillin - Lenampicillin - Sulacillin # Adverse effects ## Adverse drug reactions Common adverse drug reactions (≥1% of patients) associated with use of the penicillins include: diarrhea, nausea, rash, urticaria, and/or superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of patients) include: fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in epileptics) and/or pseudomembranous colitis.[7] Pain and inflammation at the injection site is also common for parenterally-administered benzathine benzylpenicillin, benzylpenicillin, and to a lesser extent procaine benzylpenicillin. ## Allergy/hypersensitivity Although penicillin is still the most commonly reported allergy, less than 20% of all patients who believe that they have a penicillin allergy are truly allergic to penicillin;[10] nevertheless, penicillin is still the most common cause of severe allergic drug reactions. Allergic reactions to any β-lactam antibiotic may occur in up to 10% of patients receiving that agent. Anaphylaxis will occur in approximately 0.01% of patients.[7] There is about a 5% cross-sensitivity between penicillin-derivatives, cephalosporins and carbapenems.[11] This risk warrants extreme caution with all β-lactam antibiotics in patients with a history of severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic. The PEN-FAST questions can help predict whether a patient has allergies[12]: - F: Fives years or less since an allergy event (2 points) - A: Anaphylaxis/angioedema OR - S: severe cutaneous adverse reaction (2 points) - T: Treatment required for reaction (1 point) Interpretation of the PEN-FAST: 0: Very low risk < 1% 1-2: Low risk - 5%	https://www.wikidoc.org/index.php/Benzylpenicillin
42936ef93cf26b80df62a5fa0f008e73c71b9912	wikidoc	Beta sheet	Beta sheet The β sheet (also β-pleated sheet) is the second form of regular secondary structure in proteins — the first is the alpha helix — consisting of beta strands connected laterally by three or more hydrogen bonds, forming a generally twisted, pleated sheet. A beta strand (also β-strand) is a stretch of amino acids typically 5–10 amino acids long whose peptide backbones are almost fully extended. The association of beta sheets has been implicated in the formation of protein aggregates and fibrils observed in many human diseases, notably the amyloidoses. # Nomenclature In the most common usage, β strand refers to a single continuous stretch of amino acids adopting an extended conformation and involved in hydrogen bonds; by contrast, a β sheet refers to an assembly of such strands that are hydrogen-bonded to each other. # History The first β sheet structure was proposed by William Astbury in the 1930s. He proposed the idea of hydrogen bonding between the peptide bonds of parallel or antiparallel extended β strands. However, Astbury did not have the necessary data on the bond geometry of the amino acids in order to build accurate models, especially since he did not then know that the peptide bond was planar. A refined version was proposed by Linus Pauling and Robert Corey in 1951. # Structure and orientation ## Geometry The majority of β strands are arranged adjacent to other strands and form an extensive hydrogen bond network with their neighbors in which the N-H groups in the backbone of one strand establish hydrogen bonds with the C=O groups in the backbone of the adjacent strands. In the fully extended β strand, successive side chains point straight up, then straight down, then straight up, etc. Adjacent β strands in a β sheet are aligned so that their Cα atoms are adjacent and their side chains point in the same direction. The "pleated" appearance of β strands arises from tetrahedral chemical bonding at the Cα atom; for example, if a side chain points straight up, then the bond to the \mathrm{C^{\prime}} must point slightly downwards, since its bond angle is approximately 109.5°. The pleating causes the distance between \mathrm{C^{\alpha}}_{i} and \mathrm{C^{\alpha}_{i+2}} to be approximately 6 Å, rather than the 7.6 Å (2 × 3.8 Å) expected from two fully extended trans peptide virtual bonds. The "sideways" distance between adjacent Cα atoms in hydrogen-bonded β strands is roughly 5 Å. However, β strands are rarely perfectly extended; rather, they exhibit a slight twist due to the chirality of their component amino acids. The energetically preferred dihedral angles (φ, ψ) = (–135°, 135°) (broadly, the upper left region of the Ramachandran plot) diverge somewhat from the fully extended conformation (φ, ψ) = (–180°, 180°). The twist is often associated with alternating fluctuations in the dihedral angles to prevent the individual β strands in a larger sheet from splaying apart. A good example of such a twisted β-hairpin can be seen in the protein BPTI. The side chains point outwards from the folds of the pleats, roughly perpendicularly to the plane of the sheet; successive residues point outwards on alternating faces of the sheet. ## Hydrogen bonding patterns Because peptide chains have a directionality conferred by their N-terminus and C-terminus, β strands too can be said to be directional. They are usually represented in protein topology diagrams by an arrow pointing toward the C-terminus. Adjacent β strands can form hydrogen bonds in antiparallel, parallel, or mixed arrangements. In an antiparallel arrangement, the successive β strands alternate directions so that the N-terminus of one strand is adjacent to the C-terminus of the next. This is the arrangement that produces the strongest inter-strand stability because it allows the inter-strand hydrogen bonds between carbonyls and amines to be planar, which is their preferred orientation. The peptide backbone dihedral angles (φ, ψ) are about (–140°, 135°) in antiparallel sheets. In this case, if two atoms \mathrm{C^{\alpha}_{i}} and \mathrm{C^{\alpha}_{j}} are adjacent in two hydrogen-bonded β strands, then they form two mutual backbone hydrogen bonds to each other's flanking peptide groups; this is known as a close pair of hydrogen bonds. In a parallel arrangement, all of the N-termini of successive strands are oriented in the same direction; this orientation is slightly less stable because it introduces nonplanarity in the inter-strand hydrogen bonding pattern. The dihedral angles (φ, ψ) are about (–120°, 115°) in parallel sheets. It is rare to find less than five interacting parallel strands in a motif, suggesting that a smaller number of strands may be unstable. In this case, if two atoms \mathrm{C^{\alpha}_{i}} and \mathrm{C^{\alpha}_{j}} are adjacent in two hydrogen-bonded β strands, then they do not hydrogen bond to each other; rather, one residue forms hydrogen bonds to the residues that flank the other (but not vice versa). For example, residue i may form hydrogen bonds to residues j-1 and j+1; this is known as a wide pair of hydrogen bonds. By contrast, residue j may hydrogen-bond to different residues altogether, or to none at all. Finally, an individual strand may exhibit a mixed bonding pattern, with a parallel strand on one side and an antiparallel strand on the other. Such arrangements are less common than a random distribution of orientations would suggest, indicating that this pattern is less stable than the antiparallel arrangement. The hydrogen bonding of β strands need not be perfect, but can exhibit localized disruptions known as beta bulges. The hydrogen bonds lie roughly in the plane of the sheet, with the peptide carbonyl groups pointing in alternating directions with successive residues; for comparison, successive carbonyls point in the same direction in the alpha helix. ## Amino acid propensities Large aromatic residues (Tyr, Phe and Trp) and β-branched amino acids (Thr, Val, Ile) are favored to be found in β strands in the middle of β sheets. Interestingly, different types of residues (such as Pro) are likely to be found in the edge strands in β sheets, presumably to avoid the "edge-to-edge" association between proteins that might lead to aggregation and amyloid formation. # Common structural motifs A very simple structural motif involving β sheets is the β hairpin, in which two antiparallel strands are linked by a short loop of two to five residues, of which one is frequently a glycine or a proline, both of which can assume the unusual dihedral-angle conformations required for a tight turn. However, individual strands can also be linked in more elaborate ways with long loops that may contain alpha helices or even entire protein domains. ## Greek key motif The Greek key motif consists of four adjacent antiparallel strands and their linking loops. It consists of three antiparallel strands connected by hairpins, while the fourth is adjacent to the first and linked to the third by a longer loop. This type of structure forms easily during the protein folding process. It was named after a pattern common to Greek ornamental artwork. ## The β-α-β motif Due to the chirality of their component amino acids, all strands exhibit a "right-handed" twist evident in most higher-order β sheet structures. In particular, the linking loop between two parallel strands almost always has a right-handed crossover chirality, which is strongly favored by the inherent twist of the sheet. This linking loop frequently contains a helical region, in which case it is called a β-α-β motif. A closely related motif called a β-α-β-α motif forms the basic component of the most common protein tertiary structure, the TIM barrel. ## β-meander motif A simple supersecondary protein topology composed of 2 or more consecutive antiparallel β-strands linked together by hairpin loops . This motif is common in β-sheets and can be found in several structural architectures including β-barrels and β-propellers. ## Psi-loop motif The psi-loop, Ψ-loop, motif consists of two antiparallel strands with one strand in between that is connected to both by hydrogen bonds. There are four possible strand topologies for single Ψ-loops as cited by Hutchinson et al. 1990. This motif is rare as the process resulting in its formation seems unlikely to occur during protein folding. The Ψ-loop was first identified in the aspartic protease family. # Structural architectures of proteins with beta-sheets Beta-sheets are present in all-β, α+β and α/β domains according to Structural Classification of Proteins and in many peptides or small proteins with poorly defined overal architecture. All-β domains may form β barrels, β sandwiches, β prisms, β propellers, and β-helices. # Structural topology The topology of a β sheet describes the order of hydrogen-bonded β strands along the backbone. For example, the flavodoxin fold has a five-stranded, parallel β sheet with topology 21345; thus, the edge strands are β strand 2 and β strand 5 along the backbone. Spelled out explicitly, β strand 2 is H-bonded to β strand 1, which is H-bonded to β strand 3, which is H-bonded to β strand 4, which is H-bonded to β strand 5, the other edge strand. In the same system, the Greek key motif described above has a 4123 topology. The secondary structure of a β sheet can be described roughly by giving the number of strands, their topology, and whether their hydrogen bonds are parallel or antiparallel. β sheets can be open, meaning that they have two edge strands (as in the flavodoxin fold or the immunoglobulin fold)) or they can be closed beta barrels (such as the TIM barrel). β-Barrels are often described by their stagger or shear. Some open β sheets are very curved and fold over on themselves (as in the SH3 domain) or form horseshoe shapes (as in the ribonuclease inhibitor). Open β sheets can assemble face-to-face (such as the beta-propeller domain or immunoglobulin fold) or edge-to-edge, forming one big β sheet. # Parallel β helices A β helix is formed from repeating structural units consisting of two or three short β strands linked by short loops. These units "stack" atop one another in a helical fashion so that successive repetitions of the same strand hydrogen-bond with each other in a parallel orientation. In β helices, the strands themselves are nearly planar; the resulting helical surfaces are nearly flat, forming a triangular prism shape. The two-strand helix is found in the enzyme pectate lyase. Its two loops are each six residues long and bind stabilizing calcium ions to maintain the integrity of the structure. The more complex three-strand helix contains three linking loops, of which one is consistently two residues long and the others are variable. This structure is found in bacteriophage P22 tailspike protein. # β sheets in pathology Some proteins that are disordered or helical as monomers, such as amyloid β (see amyloid plaque) can form β-sheet-rich oligomeric structures associated with pathological states. The amyloid β protein's oligomeric form is implicated as a cause of Alzheimer's. Its structure has yet to be determined in full, but recent data suggests that it may resemble an unusual two-strand β helix. The side chains from the amino acid residues found in a β sheet structure may also be arranged such that many of the adjacent sidechains on one side of the sheet are hydrophobic, while many of those adjacent to each other on the alternate side of the sheet are polar or charged (hydrophilic), which can be useful if the sheet is to form a boundary between polar/watery and nonpolar/greasy environments.	Beta sheet The β sheet (also β-pleated sheet) is the second form of regular secondary structure in proteins — the first is the alpha helix — consisting of beta strands connected laterally by three or more hydrogen bonds, forming a generally twisted, pleated sheet. A beta strand (also β-strand) is a stretch of amino acids typically 5–10 amino acids long whose peptide backbones are almost fully extended. The association of beta sheets has been implicated in the formation of protein aggregates and fibrils observed in many human diseases, notably the amyloidoses. # Nomenclature In the most common usage, β strand refers to a single continuous stretch of amino acids adopting an extended conformation and involved in hydrogen bonds; by contrast, a β sheet refers to an assembly of such strands that are hydrogen-bonded to each other. # History The first β sheet structure was proposed by William Astbury in the 1930s. He proposed the idea of hydrogen bonding between the peptide bonds of parallel or antiparallel extended β strands. However, Astbury did not have the necessary data on the bond geometry of the amino acids in order to build accurate models, especially since he did not then know that the peptide bond was planar. A refined version was proposed by Linus Pauling and Robert Corey in 1951. # Structure and orientation ## Geometry The majority of β strands are arranged adjacent to other strands and form an extensive hydrogen bond network with their neighbors in which the N-H groups in the backbone of one strand establish hydrogen bonds with the C=O groups in the backbone of the adjacent strands. In the fully extended β strand, successive side chains point straight up, then straight down, then straight up, etc. Adjacent β strands in a β sheet are aligned so that their Cα atoms are adjacent and their side chains point in the same direction. The "pleated" appearance of β strands arises from tetrahedral chemical bonding at the Cα atom; for example, if a side chain points straight up, then the bond to the <math>\mathrm{C^{\prime}}</math> must point slightly downwards, since its bond angle is approximately 109.5°. The pleating causes the distance between <math>\mathrm{C^{\alpha}}_{i}</math> and <math>\mathrm{C^{\alpha}_{i+2}}</math> to be approximately 6 Å, rather than the 7.6 Å (2 × 3.8 Å) expected from two fully extended trans peptide virtual bonds. The "sideways" distance between adjacent Cα atoms in hydrogen-bonded β strands is roughly 5 Å. However, β strands are rarely perfectly extended; rather, they exhibit a slight twist due to the chirality of their component amino acids. The energetically preferred dihedral angles (φ, ψ) = (–135°, 135°) (broadly, the upper left region of the Ramachandran plot) diverge somewhat from the fully extended conformation (φ, ψ) = (–180°, 180°).[1] The twist is often associated with alternating fluctuations in the dihedral angles to prevent the individual β strands in a larger sheet from splaying apart. A good example of such a twisted β-hairpin can be seen in the protein BPTI. The side chains point outwards from the folds of the pleats, roughly perpendicularly to the plane of the sheet; successive residues point outwards on alternating faces of the sheet. ## Hydrogen bonding patterns Because peptide chains have a directionality conferred by their N-terminus and C-terminus, β strands too can be said to be directional. They are usually represented in protein topology diagrams by an arrow pointing toward the C-terminus. Adjacent β strands can form hydrogen bonds in antiparallel, parallel, or mixed arrangements. In an antiparallel arrangement, the successive β strands alternate directions so that the N-terminus of one strand is adjacent to the C-terminus of the next. This is the arrangement that produces the strongest inter-strand stability because it allows the inter-strand hydrogen bonds between carbonyls and amines to be planar, which is their preferred orientation. The peptide backbone dihedral angles (φ, ψ) are about (–140°, 135°) in antiparallel sheets. In this case, if two atoms <math>\mathrm{C^{\alpha}_{i}}</math> and <math>\mathrm{C^{\alpha}_{j}}</math> are adjacent in two hydrogen-bonded β strands, then they form two mutual backbone hydrogen bonds to each other's flanking peptide groups; this is known as a close pair of hydrogen bonds. In a parallel arrangement, all of the N-termini of successive strands are oriented in the same direction; this orientation is slightly less stable because it introduces nonplanarity in the inter-strand hydrogen bonding pattern. The dihedral angles (φ, ψ) are about (–120°, 115°) in parallel sheets. It is rare to find less than five interacting parallel strands in a motif, suggesting that a smaller number of strands may be unstable. In this case, if two atoms <math>\mathrm{C^{\alpha}_{i}}</math> and <math>\mathrm{C^{\alpha}_{j}}</math> are adjacent in two hydrogen-bonded β strands, then they do not hydrogen bond to each other; rather, one residue forms hydrogen bonds to the residues that flank the other (but not vice versa). For example, residue <math>i</math> may form hydrogen bonds to residues <math>j-1</math> and <math>j+1</math>; this is known as a wide pair of hydrogen bonds. By contrast, residue <math>j</math> may hydrogen-bond to different residues altogether, or to none at all. Finally, an individual strand may exhibit a mixed bonding pattern, with a parallel strand on one side and an antiparallel strand on the other. Such arrangements are less common than a random distribution of orientations would suggest, indicating that this pattern is less stable than the antiparallel arrangement. The hydrogen bonding of β strands need not be perfect, but can exhibit localized disruptions known as beta bulges. The hydrogen bonds lie roughly in the plane of the sheet, with the peptide carbonyl groups pointing in alternating directions with successive residues; for comparison, successive carbonyls point in the same direction in the alpha helix. ## Amino acid propensities Large aromatic residues (Tyr, Phe and Trp) and β-branched amino acids (Thr, Val, Ile) are favored to be found in β strands in the middle of β sheets. Interestingly, different types of residues (such as Pro) are likely to be found in the edge strands in β sheets, presumably to avoid the "edge-to-edge" association between proteins that might lead to aggregation and amyloid formation. # Common structural motifs A very simple structural motif involving β sheets is the β hairpin, in which two antiparallel strands are linked by a short loop of two to five residues, of which one is frequently a glycine or a proline, both of which can assume the unusual dihedral-angle conformations required for a tight turn. However, individual strands can also be linked in more elaborate ways with long loops that may contain alpha helices or even entire protein domains. ## Greek key motif The Greek key motif consists of four adjacent antiparallel strands and their linking loops. It consists of three antiparallel strands connected by hairpins, while the fourth is adjacent to the first and linked to the third by a longer loop. This type of structure forms easily during the protein folding process. It was named after a pattern common to Greek ornamental artwork. ## The β-α-β motif Due to the chirality of their component amino acids, all strands exhibit a "right-handed" twist evident in most higher-order β sheet structures. In particular, the linking loop between two parallel strands almost always has a right-handed crossover chirality, which is strongly favored by the inherent twist of the sheet. This linking loop frequently contains a helical region, in which case it is called a β-α-β motif. A closely related motif called a β-α-β-α motif forms the basic component of the most common protein tertiary structure, the TIM barrel. ## β-meander motif A simple supersecondary protein topology composed of 2 or more consecutive antiparallel β-strands linked together by hairpin loops [1][2]. This motif is common in β-sheets and can be found in several structural architectures including β-barrels and β-propellers. ## Psi-loop motif The psi-loop, Ψ-loop, motif consists of two antiparallel strands with one strand in between that is connected to both by hydrogen bonds.[2] There are four possible strand topologies for single Ψ-loops as cited by Hutchinson et al. 1990. This motif is rare as the process resulting in its formation seems unlikely to occur during protein folding. The Ψ-loop was first identified in the aspartic protease family.[3] # Structural architectures of proteins with beta-sheets Beta-sheets are present in all-β, α+β and α/β domains according to Structural Classification of Proteins and in many peptides or small proteins with poorly defined overal architecture. All-β domains may form β barrels, β sandwiches, β prisms, β propellers, and β-helices. # Structural topology The topology of a β sheet describes the order of hydrogen-bonded β strands along the backbone. For example, the flavodoxin fold has a five-stranded, parallel β sheet with topology 21345; thus, the edge strands are β strand 2 and β strand 5 along the backbone. Spelled out explicitly, β strand 2 is H-bonded to β strand 1, which is H-bonded to β strand 3, which is H-bonded to β strand 4, which is H-bonded to β strand 5, the other edge strand. In the same system, the Greek key motif described above has a 4123 topology. The secondary structure of a β sheet can be described roughly by giving the number of strands, their topology, and whether their hydrogen bonds are parallel or antiparallel. β sheets can be open, meaning that they have two edge strands (as in the flavodoxin fold or the immunoglobulin fold)) or they can be closed beta barrels (such as the TIM barrel). β-Barrels are often described by their stagger or shear. Some open β sheets are very curved and fold over on themselves (as in the SH3 domain) or form horseshoe shapes (as in the ribonuclease inhibitor). Open β sheets can assemble face-to-face (such as the beta-propeller domain or immunoglobulin fold) or edge-to-edge, forming one big β sheet. # Parallel β helices A β helix is formed from repeating structural units consisting of two or three short β strands linked by short loops. These units "stack" atop one another in a helical fashion so that successive repetitions of the same strand hydrogen-bond with each other in a parallel orientation. In β helices, the strands themselves are nearly planar; the resulting helical surfaces are nearly flat, forming a triangular prism shape. The two-strand helix is found in the enzyme pectate lyase. Its two loops are each six residues long and bind stabilizing calcium ions to maintain the integrity of the structure. The more complex three-strand helix contains three linking loops, of which one is consistently two residues long and the others are variable. This structure is found in bacteriophage P22 tailspike protein.[4] # β sheets in pathology Some proteins that are disordered or helical as monomers, such as amyloid β (see amyloid plaque) can form β-sheet-rich oligomeric structures associated with pathological states. The amyloid β protein's oligomeric form is implicated as a cause of Alzheimer's. Its structure has yet to be determined in full, but recent data suggests that it may resemble an unusual two-strand β helix.[5] The side chains from the amino acid residues found in a β sheet structure may also be arranged such that many of the adjacent sidechains on one side of the sheet are hydrophobic, while many of those adjacent to each other on the alternate side of the sheet are polar or charged (hydrophilic), which can be useful if the sheet is to form a boundary between polar/watery and nonpolar/greasy environments.	https://www.wikidoc.org/index.php/Beta-pleated_sheet
d4b2d8de41ed356b962751a17a6b414ea6d9dfc5	wikidoc	Beta decay	Beta decay # Headline text In nuclear physics, beta decay is a type of radioactive decay in which a beta particle (an electron or a positron) is emitted. In the case of electron emission, it is referred to as "beta minus" (β−), while in the case of a positron emission as "beta plus" (β+). Beta particles move at a speed of 180,000 km/s, around 0.6c. In β− decay, the weak interaction converts a neutron (n0) into a proton (p+) while emitting an electron (e−) and an anti-neutrino (\bar{\nu}_e): At the fundamental level (as depicted in the Feynman diagram below), this is due to the conversion of a down quark to an up quark by emission of a W- boson; the W- boson subsequently decays into an electron and an anti-neutrino. In β+ decay, energy is used to convert a proton into a neutron, a positron (e+ ) and a neutrino (\nu_e): So, unlike beta minus decay, beta plus decay cannot occur in isolation, because it requires energy, the mass of the neutron being greater than the mass of the proton. Beta plus decay can only happen inside nuclei when the absolute value of the binding energy of the daughter nucleus is higher than that of the mother nucleus. The difference between these energies goes into the reaction of converting a proton into a neutron, a positron and a neutrino and into the kinetic energy of these particles. In all the cases where β+ decay is allowed energetically (and the proton is a part of a nucleus with electron shells), it is accompanied by the electron capture process, when an atomic electron is captured by a nucleus with the emission of a neutrino: But if the energy difference between initial and final states is low (less than 2mec2), then β+ decay is not energetically possible, and electron capture is the sole decay mode. If the proton and neutron are part of an atomic nucleus, these decay processes transmute one chemical element into another. For example: Beta decay does not change the number of nucleons A in the nucleus but changes only its charge Z. Thus the set of all nuclides with the same A can be introduced; these isobaric nuclides may turn into each other via beta decay. Among them, several nuclides (at least one) are beta stable, because they present local minima of the mass excess: if such a nucleus has (A, Z) numbers, the neighbour nuclei (A, Z−1) and (A, Z+1) have higher mass excess and can beta decay into (A, Z), but not vice versa. It should be noted, that a beta-stable nucleus may undergo other kinds of radioactive decay (alpha decay, for example). In nature, most isotopes are beta stable, but a few exceptions exist with half-lives so long that they have not had enough time to decay since the moment of their nucleosynthesis. One example is 40K, which undergoes all three types of beta decay (beta minus, beta plus and electron capture) with half life of 1.277×109 years. Some nuclei can undergo double beta decay (ββ decay) where the charge of the nucleus changes by two units. In most practically interesting cases, single beta decay is energetically forbidden for such nuclei, because when β and ββ decays are both allowed, the probability of β decay is (usually) much higher, preventing investigations of very rare ββ decays. Thus, ββ decay is usually studied only for beta stable nuclei. Like single beta decay, double beta decay does not change A; thus, at least one of the nuclides with some given A has to be stable with regard to both single and double beta decay. Beta decay can be considered as a perturbation as described in quantum mechanics, and thus follows Fermi's Golden Rule. # Kurie plot A Kurie plot (also known as a Fermi-Kurie plot) is a graph used in studying beta decay, in which the square root of the number of beta particles whose momenta (or energy) lie within a certain narrow range, divided by a function worked out by Fermi, is plotted against beta-particle energy; it is a straight line for allowed transitions and some forbidden transitions, in accord with the Fermi beta-decay theory. # History Historically, the study of beta decay provided the first physical evidence of the neutrino. In 1911 Lise Meitner and Otto Hahn performed an experiment that showed that the energies of electrons emitted by beta decay had a continuous rather than discrete spectrum. This was in apparent contradiction to the law of conservation of energy, as it appeared that energy was lost in the beta decay process. A second problem was that the spin of the Nitrogen-14 atom was 1, in contradiction to the Rutherford prediction of ½. In 1920-1927, Charles Drummond Ellis (along with James Chadwick and colleagues) established clearly that the beta decay spectrum is really continuous, ending all controversies. In a famous letter written in 1930 Wolfgang Pauli suggested that in addition to electrons and protons atoms also contained an extremely light neutral particle which he called the neutron. He suggested that this "neutron" was also emitted during beta decay and had simply not yet been observed. In 1931 Enrico Fermi renamed Pauli's "neutron" to neutrino, and in 1934 Fermi published a very successful model of beta decay in which neutrinos were produced. Making it simple to understand the concept of beta decay is generally represented in the following way: Where X and Y represent the parent and daughter nuclei respectively, (A= mass number, Z= atomic number, N= number of neutrons).	Beta decay # Headline text Template:Nuclear physics In nuclear physics, beta decay is a type of radioactive decay in which a beta particle (an electron or a positron) is emitted. In the case of electron emission, it is referred to as "beta minus" (β−), while in the case of a positron emission as "beta plus" (β+). Beta particles move at a speed of 180,000 km/s, around 0.6c. In β− decay, the weak interaction converts a neutron (n0) into a proton (p+) while emitting an electron (e−) and an anti-neutrino (<math>\bar{\nu}_e</math>): At the fundamental level (as depicted in the Feynman diagram below), this is due to the conversion of a down quark to an up quark by emission of a W- boson; the W- boson subsequently decays into an electron and an anti-neutrino. In β+ decay, energy is used to convert a proton into a neutron, a positron (e+ ) and a neutrino (<math>\nu_e</math>): So, unlike beta minus decay, beta plus decay cannot occur in isolation, because it requires energy, the mass of the neutron being greater than the mass of the proton. Beta plus decay can only happen inside nuclei when the absolute value of the binding energy of the daughter nucleus is higher than that of the mother nucleus. The difference between these energies goes into the reaction of converting a proton into a neutron, a positron and a neutrino and into the kinetic energy of these particles. In all the cases where β+ decay is allowed energetically (and the proton is a part of a nucleus with electron shells), it is accompanied by the electron capture process, when an atomic electron is captured by a nucleus with the emission of a neutrino: But if the energy difference between initial and final states is low (less than 2mec2), then β+ decay is not energetically possible, and electron capture is the sole decay mode. If the proton and neutron are part of an atomic nucleus, these decay processes transmute one chemical element into another. For example: Beta decay does not change the number of nucleons A in the nucleus but changes only its charge Z. Thus the set of all nuclides with the same A can be introduced; these isobaric nuclides may turn into each other via beta decay. Among them, several nuclides (at least one) are beta stable, because they present local minima of the mass excess: if such a nucleus has (A, Z) numbers, the neighbour nuclei (A, Z−1) and (A, Z+1) have higher mass excess and can beta decay into (A, Z), but not vice versa. It should be noted, that a beta-stable nucleus may undergo other kinds of radioactive decay (alpha decay, for example). In nature, most isotopes are beta stable, but a few exceptions exist with half-lives so long that they have not had enough time to decay since the moment of their nucleosynthesis. One example is 40K, which undergoes all three types of beta decay (beta minus, beta plus and electron capture) with half life of 1.277×109 years. Some nuclei can undergo double beta decay (ββ decay) where the charge of the nucleus changes by two units. In most practically interesting cases, single beta decay is energetically forbidden for such nuclei, because when β and ββ decays are both allowed, the probability of β decay is (usually) much higher, preventing investigations of very rare ββ decays. Thus, ββ decay is usually studied only for beta stable nuclei. Like single beta decay, double beta decay does not change A; thus, at least one of the nuclides with some given A has to be stable with regard to both single and double beta decay. Beta decay can be considered as a perturbation as described in quantum mechanics, and thus follows Fermi's Golden Rule. # Kurie plot Template:Section-stub A Kurie plot (also known as a Fermi-Kurie plot) is a graph used in studying beta decay, in which the square root of the number of beta particles whose momenta (or energy) lie within a certain narrow range, divided by a function worked out by Fermi, is plotted against beta-particle energy; it is a straight line for allowed transitions and some forbidden transitions, in accord with the Fermi beta-decay theory. # History Template:Section-stub Historically, the study of beta decay provided the first physical evidence of the neutrino. In 1911 Lise Meitner and Otto Hahn performed an experiment that showed that the energies of electrons emitted by beta decay had a continuous rather than discrete spectrum. This was in apparent contradiction to the law of conservation of energy, as it appeared that energy was lost in the beta decay process. A second problem was that the spin of the Nitrogen-14 atom was 1, in contradiction to the Rutherford prediction of ½. In 1920-1927, Charles Drummond Ellis (along with James Chadwick and colleagues) established clearly that the beta decay spectrum is really continuous, ending all controversies. In a famous letter written in 1930 Wolfgang Pauli suggested that in addition to electrons and protons atoms also contained an extremely light neutral particle which he called the neutron. He suggested that this "neutron" was also emitted during beta decay and had simply not yet been observed. In 1931 Enrico Fermi renamed Pauli's "neutron" to neutrino, and in 1934 Fermi published a very successful model of beta decay in which neutrinos were produced. Making it simple to understand the concept of beta decay is generally represented in the following way: Where X and Y represent the parent and daughter nuclei respectively, (A= mass number, Z= atomic number, N= number of neutrons).	https://www.wikidoc.org/index.php/Beta_decay
445a34bc4eeec0d8ce7cafe156446d1afdf223b6	wikidoc	Betrixaban	Betrixaban # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Betrixaban is a factor Xa inhibitor that is FDA approved for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE. There is a Black Box Warning for this drug as shown here. Common adverse reactions include urinary tract infection, constipation, and hypokalemia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Betrixaban is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE. The safety and effectiveness of betrixaban have not been established in patients with prosthetic heart valves because this population has not been studied. Dosing Information - The recommended dose of betrixaban is an initial single dose of 160 mg, followed by 80 mg once daily. Daily oral doses should be given at the same time of day with food. - The recommended duration of treatment is 35 to 42 days. - Severe Renal Impairment For patients with severe renal impairment, (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days. - For patients with severe renal impairment, (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily. - The recommended duration of treatment is 35 to 42 days. - Use with P-gp Inhibitors For patients receiving or starting concomitant P-gp inhibitors, the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days. - For patients receiving or starting concomitant P-gp inhibitors, the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily. - The recommended duration of treatment is 35 to 42 days. - Missed Dose If a dose of betrixaban is not taken at the scheduled time, the dose should be taken as soon as possible on the same day. The betrixaban dose should not be doubled to make up for a missed dose. - If a dose of betrixaban is not taken at the scheduled time, the dose should be taken as soon as possible on the same day. - The betrixaban dose should not be doubled to make up for a missed dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of betrixaban in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of betrixaban in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Indications and Dosage of betrixaban in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of betrixaban in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use ofbetrixaban in pediatric patients. # Contraindications Betrixaban is contraindicated in patients with: - Active pathological bleeding - Severe hypersensitivity reaction to betrixaban # Warnings - Risk of Bleeding Betrixaban increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). Advise patients of signs and symptoms of blood loss and to report them immediately and seek emergency care. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue betrixaban in patients with active pathological bleeding. There is no established way to reverse the anticoagulant effect of betrixaban, which can be expected to persist for at least 72 hours after the last dose. It is unknown whether hemodialysis removes betrixaban. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of betrixaban. - Betrixaban increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss. - Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). - Advise patients of signs and symptoms of blood loss and to report them immediately and seek emergency care. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue betrixaban in patients with active pathological bleeding. - There is no established way to reverse the anticoagulant effect of betrixaban, which can be expected to persist for at least 72 hours after the last dose. - It is unknown whether hemodialysis removes betrixaban. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of betrixaban. - Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. Do not remove an epidural catheter earlier than 72 hours after the last administration of betrixaban. Do not administer the next betrixaban dose earlier than 5 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of betrixaban for 72 hours. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention, consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. - When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. - Do not remove an epidural catheter earlier than 72 hours after the last administration of betrixaban. Do not administer the next betrixaban dose earlier than 5 hours after the removal of the catheter. - If traumatic puncture occurs, delay the administration of betrixaban for 72 hours. - Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). - If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention, consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. - Use in Patients with Severe Renal Impairment Patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) taking betrixaban may have an increased risk of bleeding events. Reduce dose of betrixaban, monitor patients closely, and promptly evaluate any signs or symptoms of blood loss in these patients. - Patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) taking betrixaban may have an increased risk of bleeding events. - Reduce dose of betrixaban, monitor patients closely, and promptly evaluate any signs or symptoms of blood loss in these patients. - Use in Patients on Concomitant P-gp Inhibitors Patients on concomitant P-gp inhibitors with betrixaban may have an increased risk of bleeding. Reduce dose of betrixaban in patients receiving or starting P-gp inhibitors. Monitor patients closely and promptly evaluate any signs or symptoms of blood loss in these patients. - Patients on concomitant P-gp inhibitors with betrixaban may have an increased risk of bleeding. Reduce dose of betrixaban in patients receiving or starting P-gp inhibitors. Monitor patients closely and promptly evaluate any signs or symptoms of blood loss in these patients. - Avoid use of betrixaban in patients with severe renal impairment receiving concomitant P-gp inhibitors. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of betrixaban was evaluated in the Acute Medically Ill Prevention with Extended Duration Betrixaban (APEX) Study, including 3,716 patients treated with betrixaban for a median of 36 days compared to 3,716 patients treated with enoxaparin for a median of 9 days. Patients in both treatment groups were followed for safety, including bleeding events, for up to 77 days. Patients randomized to the betrixaban arm received betrixaban 160 mg orally on Day 1, then 80 mg once daily for 35 to 42 days AND enoxaparin subcutaneous placebo once daily for 6 to 14 days. Patients randomized to the enoxaparin arm received enoxaparin 40 mg subcutaneously once daily for 6 to 14 days AND betrixaban placebo orally once daily for 35 to 42 days. Patients with severe renal impairment (creatinine clearance ≥ 15 and < 30 mL/min) received reduced doses of study medications (betrixaban 80 mg loading dose, then 40 mg once daily or enoxaparin 20 mg once daily) along with corresponding placebo. Patients taking a concomitant P-gp inhibitor received betrixaban 80 mg loading dose, then 40 mg once daily or enoxaparin 40 mg subcutaneously once daily for 6 to 14 days along with corresponding placebo. Hemorrhage The most common adverse reactions with betrixaban were related to bleeding (> 5%) with major bleeding occurring in less than 1% of patients. Overall, 54% of patients receiving betrixaban experienced at least one adverse reaction vs. 52% with enoxaparin. The frequency of patients reporting serious adverse reactions was similar between betrixaban (18%) and enoxaparin (17%). In the APEX trial, the most frequent reason for treatment discontinuation was bleeding, with an incidence rate of 2.4% for betrixaban vs. 1.2% for enoxaparin. The primary and secondary safety outcomes in APEX were bleeding-related events. A summary of major and clinically relevant non-major (CRNM) bleeding events in the overall safety population is shown in Table 1. Most CRNM events (86%) were mild to moderate in severity, and the majority (62%) did not require medical intervention. The incidence of fatal bleeding was the same in the betrixaban and enoxaparin treatment groups (1 in each group). A summary of major and CRNM bleeding events by dose is shown in Table 2 and Table 3. The most common adverse reactions occurring in ≥ 2% of patients are shown in Table 4. Other Adverse Reactions - Hypersensitivity reactions: one patient experienced a serious adverse reaction of moderate hypersensitivity ## Postmarketing Experience There is limited information regarding Betrixaban Postmarketing Experience in the drug label. # Drug Interactions Inhibitors of P-gp Betrixaban is a substrate of P-gp and concomitant use of P-gp inhibitors (e.g., amiodarone, azithromycin, verapamil, ketoconazole, clarithromycin) results in an increased exposure of betrixaban. Reduce the dose of betrixaban for patients receiving or starting concomitant P-gp inhibitors. Anticoagulants, Antiplatelets, and Thrombolytics Co-administration of anticoagulants, antiplatelet drugs, and thrombolytics may increase the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with anticoagulants, aspirin, other platelet aggregation inhibitors, and/or NSAIDs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary There are no data with the use of betrixaban in pregnant women, but treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Betrixaban was studied in reproductive and developmental toxicology studies in rats and rabbits during the period of organogenesis at exposures up to 44 times the recommended clinical dose of 80 mg daily. Although betrixaban was not associated with adverse developmental fetal outcomes in animals, maternal toxicity (i.e., hemorrhage) was identified in these studies. Betrixaban should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no adverse embryofetal or teratogenic effects were seen when betrixaban was administered orally at doses up to 200 mg/kg/day, or 44 times the human dose of 80 mg/day when based on AUC. In rabbits, no adverse embryofetal or teratogenic effects were seen at doses up to 45 mg/kg/day, or 35 times the human exposure at a dose of 80 mg/day when based on AUC. Pregnant rabbits administered the highest dose of 150 mg/kg/day were terminated prematurely due to excessive maternal toxicities. Upon post-mortem examination, early and/or late resorptions and fetal deaths were observed at the 150 mg/kg dose, which may be linked to hemorrhage observed in various organs including the reproductive tract. In a rat pre-and-post-natal developmental study, betrixaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 200 mg/kg/day. Maternal toxicities (including decreased body weight gain and food consumption and red/brown perivaginal substance) were observed at 200 mg/kg/day, which is approximately 44 times the human exposure when based on AUC. At a maternal dose up to 200 mg/kg/day, betrixaban did not have adverse effects on sexual maturation, reproductive performance, and behavioral development of the F1 generation. Clinical Considerations Maternal Adverse Reactions Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Consider the risks of bleeding and of stroke in using betrixaban in this setting. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Betrixaban in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Betrixaban during labor and delivery. ### Nursing Mothers Risk Summary No data are available regarding the presence of betrixaban or its metabolites in human milk, the effects of the drug on the breast-fed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for betrixaban and any potential adverse effects on the breast-fed child from betrixaban or from the underlying maternal condition. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use Of the total number of patients in the APEX clinical study 90% were 65 years and over, while 68.6% were greater than or equal to 75 years. No clinically significant differences in safety or effectiveness were observed between older and younger patients. ### Gender There is no FDA guidance on the use of Betrixaban with respect to specific gender populations. ### Race There is no FDA guidance on the use of Betrixaban with respect to specific racial populations. ### Renal Impairment Patients with severe renal impairment (CrCl ≥ 15 to 30 mL/min, computed by Cockcroft-Gault using actual body weight). ### Hepatic Impairment Betrixaban has not been evaluated in patients with hepatic impairment, because these patients may have intrinsic coagulation abnormalities. Therefore, the use of betrixaban is not recommended in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Betrixaban in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Betrixaban in patients who are immunocompromised. # Administration and Monitoring ### Administration The recommended duration of treatment is 35 to 42 days. ### Monitoring There is limited information regarding Betrixaban Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Betrixaban and IV administrations. # Overdosage Overdose of betrixaban increases the risk of bleeding. A specific reversal agent for betrixaban is not available. There is no experience with hemodialysis in individuals receiving betrixaban. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of betrixaban. # Pharmacology ## Mechanism of Action Betrixaban is an oral FXa inhibitor that selectively blocks the active site of FXa and does not require a cofactor (such as Anti-thrombin III) for activity. Betrixaban inhibits free FXa and prothrombinase activity. By directly inhibiting FXa, betrixaban decreases thrombin generation (TG). Betrixaban has no direct effect on platelet aggregation. ## Structure Betrixaban, a factor Xa (FXa) inhibitor, is chemically described as N-(5-chloropyridin-2-yl)-2--5-methoxybenzamide maleate. Its molecular formula (as maleate salt) is C27H26ClN5O7, which corresponds to a molecular weight of 567.98. Betrixaban (maleate salt) has the following structural formula: ## Pharmacodynamics Inhibition of FXa by betrixaban results in an inhibition of thrombin generation at clinically relevant concentrations, and the maximum inhibition of thrombin generation coincides with the time of peak betrixaban concentrations. Cardiac Electrophysiology In a study that evaluated the effect of betrixaban on the QT interval, a concentration-dependent increase in the QTc interval was observed. Based on the observed concentration-QTc relationship a mean (upper 95% CI) QTc prolongation of 4 ms (5 ms) is predicted for 80 mg betrixaban and 13 ms (16 ms) for a 4.7-fold increase in exposure. ## Pharmacokinetics Within the anticipated therapeutic dose range, a two-fold increase in dose resulted in a three-fold increase in exposure in the single ascending dose study. A two-fold increase in betrixaban exposure was observed after repeat dosing, and the time to steady-state is 6 days (without an initial loading dose). Absorption The oral bioavailability of betrixaban for an 80 mg dose is 34%, and peak concentrations occurred within 3 to 4 hours. Betrixaban is also a substrate of P-gp. Effect of Food When administered with a low-fat (900 calories, 20% fat) or high-fat (900 calories, 60% fat) meal, Cmax and AUC were reduced as compared to the fasting state by an average of 70% and 61% for low-fat and 50% and 48% for high-fat, respectively. The effect of food on betrixaban PK could be observed for up to 6 hours after meal intake. Distribution The apparent volume of distribution is 32 L/kg. In vitro plasma protein binding is 60%. Elimination The effective half-life of betrixaban is 19 to 27 hours. Metabolism Unchanged betrixaban is the predominant component found in human plasma. Two inactive major metabolites formed by CYP-independent hydrolysis comprise the other components in plasma, accounting for 15 to 18% of the circulating drug-related material. Less than 1% of the minor metabolites could be formed via metabolism by the following CYP enzymes; CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Excretion Following oral administration of radio-labeled betrixaban approximately 85% of the administered compound was recovered in the feces and 11% recovered in the urine. In a study of intravenous betrixaban, a median value of 17.8% of the absorbed dose was observed as unchanged betrixaban in urine. Specific Populations Male and Female Patients No clinically significant changes in betrixaban pharmacokinetics were observed between males and females. Patients with Renal Impairment In a dedicated renal impairment study mean AUC0-24 on day 8 was increased by 1.89, 2.27 and 2.63-fold in mild (eGFRMDRD ≥ 60 to < 90 mL/min/1.73 m2), moderate (eGFRMDRD ≥ 30 to < 60 mL/min/1.73 m2) and severe (eGFRMDRD ≥ 15 to < 30 mL/min/1.73 m2) renal impaired patients respectively compared to healthy volunteers. Patients with Hepatic Impairment Studies with betrixaban in patients with hepatic impairment have not been conducted and the impact of hepatic impairment on the exposure to betrixaban has not been evaluated. Drug Interaction Studies The effects of coadministered drugs on the pharmacokinetics of betrixaban exposure based on drug interaction studies are summarized in Figure 1. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with betrixaban have not been performed. Betrixaban was not mutagenic in bacteria (Ames-Test) or clastogenic in Chinese hamster ovary cells in vitro or in the rat micronucleus test in vivo. In a study to assess fertility and early embryonic development to implantation, oral doses of betrixaban were administered to male and female rats. There was no evidence that betrixaban up to 150 mg/kg/day adversely affected male or female fertility, reproductive performance, or embryo-fetal viability. # Clinical Studies The clinical evidence for the effectiveness of betrixaban is derived from the APEX clinical trial . APEX was a randomized, double-blind, multinational study comparing extended duration betrixaban (35 to 42 days) to short duration of enoxaparin (6 to 14 days) in the prevention of venous thromboembolic events (VTE) in an acutely medically ill hospitalized population with risk factors for VTE. Eligible patients included adults who were at least 40 years of age, hospitalized for an acute medical illness, at risk for VTE due to moderate or severe immobility, and had additional risk factors for VTE (described below). Expected duration of hospitalization was at least 3 days and patients were expected to be moderately or severely immobilized for at least 24 hours. The causes for hospitalization included heart failure, respiratory failure, infectious disease, rheumatic disease, or ischemic stroke. At study initiation eligible patients were required to have one of the following additional risk factors for VTE: - ≥ 75 years of age, - 60 through 74 years of age with D-dimer ≥ 2 ULN, or - 40 through 59 years of age with D-dimer ≥ 2 ULN and a history of either VTE or cancer A total of 7,513 patients were randomized 1:1 to: - Betrixaban arm (betrixaban 160 mg orally on Day 1, then 80 mg once daily for 35 to 42 days AND enoxaparin subcutaneous placebo once daily for 6 to 14 days), OR - Enoxaparin arm (enoxaparin 40 mg subcutaneously once daily for 6 to 14 days AND betrixaban placebo orally once daily for 35 to 42 days). Patients with severe renal impairment (creatinine clearance ≥ 15 and < 30 mL/min) received reduced doses of study medications (betrixaban 80 mg loading dose, then 40 mg once daily or enoxaparin 20 mg once daily) along with corresponding placebo. Patients taking a concomitant P-gp inhibitor received betrixaban 80 mg loading dose, then 40 mg once daily or enoxaparin 40 mg subcutaneously once daily for 6 to 14 days along with corresponding placebo. Baseline characteristics were balanced between the treatment groups. The population was 55% female, 93% White, 2% Black, 0.2% Asian, and 5% others. The most prevalent acute medical illness at hospitalization was acutely decompensated heart failure (45%), followed by acute infection without septic shock (29%), acute respiratory failure (12%), acute ischemic stroke (11%) and acute rheumatic disorders (3%). The mean and median ages were 76.4 and 77 years, respectively, with 68% of patients ≥ 75 years of age, 97% were severely immobilized at study entry, and 62% had D-dimer ≥ 2 × ULN. While the APEX Study was ongoing (after 35% enrollment), the study was amended to restrict further enrollment to patients ≥ 75 years of age or with D-dimer values ≥ 2 × ULN. The APEX trial excluded patients whose condition required prolonged anticoagulation (e.g., concurrent VTE, atrial fibrillation, cardiac valve prosthesis), were at increased risk of bleeding, had liver dysfunction, were on dual antiplatelet therapy, or patients who had both severe renal insufficiency (CrCl 15-29 ml/min) and required the concomitant use of a P-gp inhibitor. The efficacy of betrixaban was based upon the composite outcome of the occurrence of any of the following events up to Day 35 visit: - Asymptomatic proximal Deep Vein Thrombosis (DVT) (detected by ultrasound), - Symptomatic proximal or distal DVT, - Non-fatal Pulmonary Embolism (PE), or - VTE-related death Efficacy analyses were performed based on the modified Intent-to-Treat (mITT) population. The mITT population consisted of all patients who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy outcome components. A total of 7,441 patients (N=3,721 for betrixaban and N=3,720 for enoxaparin) were included in the mITT population. The efficacy results for the APEX trial are provided in Table 5 below. For patients with D-dimer ≥ 2 ULN at baseline, the event rate is 5.7% in the betrixaban arm vs. 7.2% in the enoxaparin arm (relative risk = 0.79, 95% CI ). For patients with D-dimer ≥ 2 ULN at baseline or age ≥ 75 years, the event rate is 4.7% in the betrixaban arm vs. 6.0% in the enoxaparin arm (relative risk = 0.78, 95% CI ). Results for the primary efficacy analysis for subjects that were stratified at randomization to the 80 mg betrixaban dose group in the mITT population are shown in Table 6 below. Patients who were randomized to receive 40 mg betrixaban (those with severe renal impairment or receiving P-gp inhibitors), had VTE rates similar to the enoxaparin arm (6 to 14 days followed by placebo) shown in Table 7 below. # How Supplied Betrixaban capsules are available as listed below. The 40 mg size 4 capsules are light grey with 40 printed in black, and have a light blue cap with PTLA printed in white. - Bottles of 100 (NDC 69853-0202-1) The 80 mg size 2 capsules are light grey with 80 printed in black, and have a blue cap with PTLA printed in white. - Bottles of 100 (NDC 69853-0201-1) ## Storage Store at room temperature; 20°C to 25°C (68°F to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). - Risk of Bleeding Advise patients that it might take longer than usual for bleeding to stop, and that they may bruise or bleed more easily when treated with betrixaban. Instruct patients to report any unusual bleeding to their physician. Instruct patients to tell their physicians and dentists that they are taking betrixaban, and/or any other products known to affect bleeding (including nonprescription products, such as aspirin or NSAIDs), before any surgery or medical or dental procedure is scheduled and before any new drug is taken. - Advise patients that it might take longer than usual for bleeding to stop, and that they may bruise or bleed more easily when treated with betrixaban. - Instruct patients to report any unusual bleeding to their physician. - Instruct patients to tell their physicians and dentists that they are taking betrixaban, and/or any other products known to affect bleeding (including nonprescription products, such as aspirin or NSAIDs), before any surgery or medical or dental procedure is scheduled and before any new drug is taken. - Use in Patients with Severe Renal Impairment Advise patients that the risk of bleeding is higher in people who have severe kidney problems (severe renal impairment). - Advise patients that the risk of bleeding is higher in people who have severe kidney problems (severe renal impairment). - Spinal/Epidural Hematoma Advise patients having neuraxial anesthesia or spinal puncture to watch for signs and symptoms of spinal or epidural hematomas, such as numbness or weakness of the legs, or bowel or bladder dysfunction. Instruct patients to contact their physician immediately if any of these symptoms occur. - Advise patients having neuraxial anesthesia or spinal puncture to watch for signs and symptoms of spinal or epidural hematomas, such as numbness or weakness of the legs, or bowel or bladder dysfunction. - Instruct patients to contact their physician immediately if any of these symptoms occur. - Pregnancy and Lactation Advise female patients to inform their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed during treatment with betrixaban. - Advise female patients to inform their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed during treatment with betrixaban. - How to Take Betrixaban Instruct patients to take betrixaban with food, and instruct patients on what to do if a dose is missed. - Instruct patients to take betrixaban with food, and instruct patients on what to do if a dose is missed. # Precautions with Alcohol Alcohol-Betrixaban interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names BEVYXXA # Look-Alike Drug Names There is limited information regarding Betrixaban Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Betrixaban Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Allison Tu [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Betrixaban is a factor Xa inhibitor that is FDA approved for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE. There is a Black Box Warning for this drug as shown here. Common adverse reactions include urinary tract infection, constipation, and hypokalemia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Betrixaban is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE. The safety and effectiveness of betrixaban have not been established in patients with prosthetic heart valves because this population has not been studied. Dosing Information - The recommended dose of betrixaban is an initial single dose of 160 mg, followed by 80 mg once daily. Daily oral doses should be given at the same time of day with food. - The recommended duration of treatment is 35 to 42 days. - Severe Renal Impairment For patients with severe renal impairment, (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days. - For patients with severe renal impairment, (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily. - The recommended duration of treatment is 35 to 42 days. - Use with P-gp Inhibitors For patients receiving or starting concomitant P-gp inhibitors, the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days. - For patients receiving or starting concomitant P-gp inhibitors, the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily. - The recommended duration of treatment is 35 to 42 days. - Missed Dose If a dose of betrixaban is not taken at the scheduled time, the dose should be taken as soon as possible on the same day. The betrixaban dose should not be doubled to make up for a missed dose. - If a dose of betrixaban is not taken at the scheduled time, the dose should be taken as soon as possible on the same day. - The betrixaban dose should not be doubled to make up for a missed dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of betrixaban in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of betrixaban in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Indications and Dosage of betrixaban in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of betrixaban in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use ofbetrixaban in pediatric patients. # Contraindications Betrixaban is contraindicated in patients with: - Active pathological bleeding - Severe hypersensitivity reaction to betrixaban # Warnings - Risk of Bleeding Betrixaban increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). Advise patients of signs and symptoms of blood loss and to report them immediately and seek emergency care. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue betrixaban in patients with active pathological bleeding. There is no established way to reverse the anticoagulant effect of betrixaban, which can be expected to persist for at least 72 hours after the last dose. It is unknown whether hemodialysis removes betrixaban. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of betrixaban. - Betrixaban increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss. - Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). - Advise patients of signs and symptoms of blood loss and to report them immediately and seek emergency care. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue betrixaban in patients with active pathological bleeding. - There is no established way to reverse the anticoagulant effect of betrixaban, which can be expected to persist for at least 72 hours after the last dose. - It is unknown whether hemodialysis removes betrixaban. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of betrixaban. - Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. Do not remove an epidural catheter earlier than 72 hours after the last administration of betrixaban. Do not administer the next betrixaban dose earlier than 5 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of betrixaban for 72 hours. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention, consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. - When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. - Do not remove an epidural catheter earlier than 72 hours after the last administration of betrixaban. Do not administer the next betrixaban dose earlier than 5 hours after the removal of the catheter. - If traumatic puncture occurs, delay the administration of betrixaban for 72 hours. - Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). - If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention, consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. - Use in Patients with Severe Renal Impairment Patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) taking betrixaban may have an increased risk of bleeding events. Reduce dose of betrixaban, monitor patients closely, and promptly evaluate any signs or symptoms of blood loss in these patients. - Patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) taking betrixaban may have an increased risk of bleeding events. - Reduce dose of betrixaban, monitor patients closely, and promptly evaluate any signs or symptoms of blood loss in these patients. - Use in Patients on Concomitant P-gp Inhibitors Patients on concomitant P-gp inhibitors with betrixaban may have an increased risk of bleeding. Reduce dose of betrixaban in patients receiving or starting P-gp inhibitors. Monitor patients closely and promptly evaluate any signs or symptoms of blood loss in these patients. - Patients on concomitant P-gp inhibitors with betrixaban may have an increased risk of bleeding. Reduce dose of betrixaban in patients receiving or starting P-gp inhibitors. Monitor patients closely and promptly evaluate any signs or symptoms of blood loss in these patients. - Avoid use of betrixaban in patients with severe renal impairment receiving concomitant P-gp inhibitors. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of betrixaban was evaluated in the Acute Medically Ill Prevention with Extended Duration Betrixaban (APEX) Study, including 3,716 patients treated with betrixaban for a median of 36 days compared to 3,716 patients treated with enoxaparin for a median of 9 days. Patients in both treatment groups were followed for safety, including bleeding events, for up to 77 days. Patients randomized to the betrixaban arm received betrixaban 160 mg orally on Day 1, then 80 mg once daily for 35 to 42 days AND enoxaparin subcutaneous placebo once daily for 6 to 14 days. Patients randomized to the enoxaparin arm received enoxaparin 40 mg subcutaneously once daily for 6 to 14 days AND betrixaban placebo orally once daily for 35 to 42 days. Patients with severe renal impairment (creatinine clearance ≥ 15 and < 30 mL/min) received reduced doses of study medications (betrixaban 80 mg loading dose, then 40 mg once daily or enoxaparin 20 mg once daily) along with corresponding placebo. Patients taking a concomitant P-gp inhibitor received betrixaban 80 mg loading dose, then 40 mg once daily or enoxaparin 40 mg subcutaneously once daily for 6 to 14 days along with corresponding placebo. Hemorrhage The most common adverse reactions with betrixaban were related to bleeding (> 5%) with major bleeding occurring in less than 1% of patients. Overall, 54% of patients receiving betrixaban experienced at least one adverse reaction vs. 52% with enoxaparin. The frequency of patients reporting serious adverse reactions was similar between betrixaban (18%) and enoxaparin (17%). In the APEX trial, the most frequent reason for treatment discontinuation was bleeding, with an incidence rate of 2.4% for betrixaban vs. 1.2% for enoxaparin. The primary and secondary safety outcomes in APEX were bleeding-related events. A summary of major and clinically relevant non-major (CRNM) bleeding events in the overall safety population is shown in Table 1. Most CRNM events (86%) were mild to moderate in severity, and the majority (62%) did not require medical intervention. The incidence of fatal bleeding was the same in the betrixaban and enoxaparin treatment groups (1 in each group). A summary of major and CRNM bleeding events by dose is shown in Table 2 and Table 3. The most common adverse reactions occurring in ≥ 2% of patients are shown in Table 4. Other Adverse Reactions - Hypersensitivity reactions: one patient experienced a serious adverse reaction of moderate hypersensitivity ## Postmarketing Experience There is limited information regarding Betrixaban Postmarketing Experience in the drug label. # Drug Interactions Inhibitors of P-gp Betrixaban is a substrate of P-gp and concomitant use of P-gp inhibitors (e.g., amiodarone, azithromycin, verapamil, ketoconazole, clarithromycin) results in an increased exposure of betrixaban. Reduce the dose of betrixaban for patients receiving or starting concomitant P-gp inhibitors. Anticoagulants, Antiplatelets, and Thrombolytics Co-administration of anticoagulants, antiplatelet drugs, and thrombolytics may increase the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with anticoagulants, aspirin, other platelet aggregation inhibitors, and/or NSAIDs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary There are no data with the use of betrixaban in pregnant women, but treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Betrixaban was studied in reproductive and developmental toxicology studies in rats and rabbits during the period of organogenesis at exposures up to 44 times the recommended clinical dose of 80 mg daily. Although betrixaban was not associated with adverse developmental fetal outcomes in animals, maternal toxicity (i.e., hemorrhage) was identified in these studies. Betrixaban should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no adverse embryofetal or teratogenic effects were seen when betrixaban was administered orally at doses up to 200 mg/kg/day, or 44 times the human dose of 80 mg/day when based on AUC. In rabbits, no adverse embryofetal or teratogenic effects were seen at doses up to 45 mg/kg/day, or 35 times the human exposure at a dose of 80 mg/day when based on AUC. Pregnant rabbits administered the highest dose of 150 mg/kg/day were terminated prematurely due to excessive maternal toxicities. Upon post-mortem examination, early and/or late resorptions and fetal deaths were observed at the 150 mg/kg dose, which may be linked to hemorrhage observed in various organs including the reproductive tract. In a rat pre-and-post-natal developmental study, betrixaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 200 mg/kg/day. Maternal toxicities (including decreased body weight gain and food consumption and red/brown perivaginal substance) were observed at 200 mg/kg/day, which is approximately 44 times the human exposure when based on AUC. At a maternal dose up to 200 mg/kg/day, betrixaban did not have adverse effects on sexual maturation, reproductive performance, and behavioral development of the F1 generation. Clinical Considerations Maternal Adverse Reactions Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Consider the risks of bleeding and of stroke in using betrixaban in this setting. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Betrixaban in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Betrixaban during labor and delivery. ### Nursing Mothers Risk Summary No data are available regarding the presence of betrixaban or its metabolites in human milk, the effects of the drug on the breast-fed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for betrixaban and any potential adverse effects on the breast-fed child from betrixaban or from the underlying maternal condition. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use Of the total number of patients in the APEX clinical study 90% were 65 years and over, while 68.6% were greater than or equal to 75 years. No clinically significant differences in safety or effectiveness were observed between older and younger patients. ### Gender There is no FDA guidance on the use of Betrixaban with respect to specific gender populations. ### Race There is no FDA guidance on the use of Betrixaban with respect to specific racial populations. ### Renal Impairment Patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) may have an increased risk of bleeding events. Reduce the betrixaban dose for patients with severe renal impairment. Monitor patients closely and promptly evaluate any signs or symptoms of blood loss in these patients. No dose adjustment is needed for mild or moderate renal impairment (CrCl > 30 mL/min, computed by Cockcroft-Gault using actual body weight). ### Hepatic Impairment Betrixaban has not been evaluated in patients with hepatic impairment, because these patients may have intrinsic coagulation abnormalities. Therefore, the use of betrixaban is not recommended in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Betrixaban in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Betrixaban in patients who are immunocompromised. # Administration and Monitoring ### Administration The recommended duration of treatment is 35 to 42 days. ### Monitoring There is limited information regarding Betrixaban Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Betrixaban and IV administrations. # Overdosage Overdose of betrixaban increases the risk of bleeding. A specific reversal agent for betrixaban is not available. There is no experience with hemodialysis in individuals receiving betrixaban. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of betrixaban. # Pharmacology ## Mechanism of Action Betrixaban is an oral FXa inhibitor that selectively blocks the active site of FXa and does not require a cofactor (such as Anti-thrombin III) for activity. Betrixaban inhibits free FXa and prothrombinase activity. By directly inhibiting FXa, betrixaban decreases thrombin generation (TG). Betrixaban has no direct effect on platelet aggregation. ## Structure Betrixaban, a factor Xa (FXa) inhibitor, is chemically described as N-(5-chloropyridin-2-yl)-2-[4-(N,N-dimethylcarbamimidoyl)-benzoylamino]-5-methoxybenzamide maleate. Its molecular formula (as maleate salt) is C27H26ClN5O7, which corresponds to a molecular weight of 567.98. Betrixaban (maleate salt) has the following structural formula: ## Pharmacodynamics Inhibition of FXa by betrixaban results in an inhibition of thrombin generation at clinically relevant concentrations, and the maximum inhibition of thrombin generation coincides with the time of peak betrixaban concentrations. Cardiac Electrophysiology In a study that evaluated the effect of betrixaban on the QT interval, a concentration-dependent increase in the QTc interval was observed. Based on the observed concentration-QTc relationship a mean (upper 95% CI) QTc prolongation of 4 ms (5 ms) is predicted for 80 mg betrixaban and 13 ms (16 ms) for a 4.7-fold increase in exposure. ## Pharmacokinetics Within the anticipated therapeutic dose range, a two-fold increase in dose resulted in a three-fold increase in exposure in the single ascending dose study. A two-fold increase in betrixaban exposure was observed after repeat dosing, and the time to steady-state is 6 days (without an initial loading dose). Absorption The oral bioavailability of betrixaban for an 80 mg dose is 34%, and peak concentrations occurred within 3 to 4 hours. Betrixaban is also a substrate of P-gp. Effect of Food When administered with a low-fat (900 calories, 20% fat) or high-fat (900 calories, 60% fat) meal, Cmax and AUC were reduced as compared to the fasting state by an average of 70% and 61% for low-fat and 50% and 48% for high-fat, respectively. The effect of food on betrixaban PK could be observed for up to 6 hours after meal intake. Distribution The apparent volume of distribution is 32 L/kg. In vitro plasma protein binding is 60%. Elimination The effective half-life of betrixaban is 19 to 27 hours. Metabolism Unchanged betrixaban is the predominant component found in human plasma. Two inactive major metabolites formed by CYP-independent hydrolysis comprise the other components in plasma, accounting for 15 to 18% of the circulating drug-related material. Less than 1% of the minor metabolites could be formed via metabolism by the following CYP enzymes; CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Excretion Following oral administration of radio-labeled betrixaban approximately 85% of the administered compound was recovered in the feces and 11% recovered in the urine. In a study of intravenous betrixaban, a median value of 17.8% of the absorbed dose was observed as unchanged betrixaban in urine. Specific Populations Male and Female Patients No clinically significant changes in betrixaban pharmacokinetics were observed between males and females. Patients with Renal Impairment In a dedicated renal impairment study mean AUC0-24 on day 8 was increased by 1.89, 2.27 and 2.63-fold in mild (eGFRMDRD ≥ 60 to < 90 mL/min/1.73 m2), moderate (eGFRMDRD ≥ 30 to < 60 mL/min/1.73 m2) and severe (eGFRMDRD ≥ 15 to < 30 mL/min/1.73 m2) renal impaired patients respectively compared to healthy volunteers. Patients with Hepatic Impairment Studies with betrixaban in patients with hepatic impairment have not been conducted and the impact of hepatic impairment on the exposure to betrixaban has not been evaluated. Drug Interaction Studies The effects of coadministered drugs on the pharmacokinetics of betrixaban exposure based on drug interaction studies are summarized in Figure 1. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with betrixaban have not been performed. Betrixaban was not mutagenic in bacteria (Ames-Test) or clastogenic in Chinese hamster ovary cells in vitro or in the rat micronucleus test in vivo. In a study to assess fertility and early embryonic development to implantation, oral doses of betrixaban were administered to male and female rats. There was no evidence that betrixaban up to 150 mg/kg/day adversely affected male or female fertility, reproductive performance, or embryo-fetal viability. # Clinical Studies The clinical evidence for the effectiveness of betrixaban is derived from the APEX clinical trial [NCT01583218]. APEX was a randomized, double-blind, multinational study comparing extended duration betrixaban (35 to 42 days) to short duration of enoxaparin (6 to 14 days) in the prevention of venous thromboembolic events (VTE) in an acutely medically ill hospitalized population with risk factors for VTE. Eligible patients included adults who were at least 40 years of age, hospitalized for an acute medical illness, at risk for VTE due to moderate or severe immobility, and had additional risk factors for VTE (described below). Expected duration of hospitalization was at least 3 days and patients were expected to be moderately or severely immobilized for at least 24 hours. The causes for hospitalization included heart failure, respiratory failure, infectious disease, rheumatic disease, or ischemic stroke. At study initiation eligible patients were required to have one of the following additional risk factors for VTE: - ≥ 75 years of age, - 60 through 74 years of age with D-dimer ≥ 2 ULN, or - 40 through 59 years of age with D-dimer ≥ 2 ULN and a history of either VTE or cancer A total of 7,513 patients were randomized 1:1 to: - Betrixaban arm (betrixaban 160 mg orally on Day 1, then 80 mg once daily for 35 to 42 days AND enoxaparin subcutaneous placebo once daily for 6 to 14 days), OR - Enoxaparin arm (enoxaparin 40 mg subcutaneously once daily for 6 to 14 days AND betrixaban placebo orally once daily for 35 to 42 days). Patients with severe renal impairment (creatinine clearance ≥ 15 and < 30 mL/min) received reduced doses of study medications (betrixaban 80 mg loading dose, then 40 mg once daily or enoxaparin 20 mg once daily) along with corresponding placebo. Patients taking a concomitant P-gp inhibitor received betrixaban 80 mg loading dose, then 40 mg once daily or enoxaparin 40 mg subcutaneously once daily for 6 to 14 days along with corresponding placebo. Baseline characteristics were balanced between the treatment groups. The population was 55% female, 93% White, 2% Black, 0.2% Asian, and 5% others. The most prevalent acute medical illness at hospitalization was acutely decompensated heart failure (45%), followed by acute infection without septic shock (29%), acute respiratory failure (12%), acute ischemic stroke (11%) and acute rheumatic disorders (3%). The mean and median ages were 76.4 and 77 years, respectively, with 68% of patients ≥ 75 years of age, 97% were severely immobilized at study entry, and 62% had D-dimer ≥ 2 × ULN. While the APEX Study was ongoing (after 35% enrollment), the study was amended to restrict further enrollment to patients ≥ 75 years of age or with D-dimer values ≥ 2 × ULN. The APEX trial excluded patients whose condition required prolonged anticoagulation (e.g., concurrent VTE, atrial fibrillation, cardiac valve prosthesis), were at increased risk of bleeding, had liver dysfunction, were on dual antiplatelet therapy, or patients who had both severe renal insufficiency (CrCl 15-29 ml/min) and required the concomitant use of a P-gp inhibitor. The efficacy of betrixaban was based upon the composite outcome of the occurrence of any of the following events up to Day 35 visit: - Asymptomatic proximal Deep Vein Thrombosis (DVT) (detected by ultrasound), - Symptomatic proximal or distal DVT, - Non-fatal Pulmonary Embolism (PE), or - VTE-related death Efficacy analyses were performed based on the modified Intent-to-Treat (mITT) population. The mITT population consisted of all patients who had taken at least one dose of study drug and who had follow-up assessment data on one or more primary or secondary efficacy outcome components. A total of 7,441 patients (N=3,721 for betrixaban and N=3,720 for enoxaparin) were included in the mITT population. The efficacy results for the APEX trial are provided in Table 5 below. For patients with D-dimer ≥ 2 ULN at baseline, the event rate is 5.7% in the betrixaban arm vs. 7.2% in the enoxaparin arm (relative risk = 0.79, 95% CI [0.63, 0.98]). For patients with D-dimer ≥ 2 ULN at baseline or age ≥ 75 years, the event rate is 4.7% in the betrixaban arm vs. 6.0% in the enoxaparin arm (relative risk = 0.78, 95% CI [0.64, 0.96]). Results for the primary efficacy analysis for subjects that were stratified at randomization to the 80 mg betrixaban dose group in the mITT population are shown in Table 6 below. Patients who were randomized to receive 40 mg betrixaban (those with severe renal impairment or receiving P-gp inhibitors), had VTE rates similar to the enoxaparin arm (6 to 14 days followed by placebo) shown in Table 7 below. # How Supplied Betrixaban capsules are available as listed below. The 40 mg size 4 capsules are light grey with 40 printed in black, and have a light blue cap with PTLA printed in white. - Bottles of 100 (NDC 69853-0202-1) The 80 mg size 2 capsules are light grey with 80 printed in black, and have a blue cap with PTLA printed in white. - Bottles of 100 (NDC 69853-0201-1) ## Storage Store at room temperature; 20°C to 25°C (68°F to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). - Risk of Bleeding Advise patients that it might take longer than usual for bleeding to stop, and that they may bruise or bleed more easily when treated with betrixaban. Instruct patients to report any unusual bleeding to their physician. Instruct patients to tell their physicians and dentists that they are taking betrixaban, and/or any other products known to affect bleeding (including nonprescription products, such as aspirin or NSAIDs), before any surgery or medical or dental procedure is scheduled and before any new drug is taken. - Advise patients that it might take longer than usual for bleeding to stop, and that they may bruise or bleed more easily when treated with betrixaban. - Instruct patients to report any unusual bleeding to their physician. - Instruct patients to tell their physicians and dentists that they are taking betrixaban, and/or any other products known to affect bleeding (including nonprescription products, such as aspirin or NSAIDs), before any surgery or medical or dental procedure is scheduled and before any new drug is taken. - Use in Patients with Severe Renal Impairment Advise patients that the risk of bleeding is higher in people who have severe kidney problems (severe renal impairment). - Advise patients that the risk of bleeding is higher in people who have severe kidney problems (severe renal impairment). - Spinal/Epidural Hematoma Advise patients having neuraxial anesthesia or spinal puncture to watch for signs and symptoms of spinal or epidural hematomas, such as numbness or weakness of the legs, or bowel or bladder dysfunction. Instruct patients to contact their physician immediately if any of these symptoms occur. - Advise patients having neuraxial anesthesia or spinal puncture to watch for signs and symptoms of spinal or epidural hematomas, such as numbness or weakness of the legs, or bowel or bladder dysfunction. - Instruct patients to contact their physician immediately if any of these symptoms occur. - Pregnancy and Lactation Advise female patients to inform their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed during treatment with betrixaban. - Advise female patients to inform their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed during treatment with betrixaban. - How to Take Betrixaban Instruct patients to take betrixaban with food, and instruct patients on what to do if a dose is missed. - Instruct patients to take betrixaban with food, and instruct patients on what to do if a dose is missed. # Precautions with Alcohol Alcohol-Betrixaban interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names BEVYXXA # Look-Alike Drug Names There is limited information regarding Betrixaban Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Betrixaban
ca4ca7884248e662758141fad59cbb2a68d93c08	wikidoc	Bexarotene	Bexarotene # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Bexarotene is an antineoplastic agent that is FDA approved for the treatment of cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies.. Common adverse reactions include rash, pruritus, skin disorder, and pain, peripheral edema, dry skin, photosensitivity, hypothyroidism, abdominal pain, nausea, asthenia, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Bexarotene 1% is indicated for the topical treatment of cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies. - Bexarotene should be initially applied once every other day for the first week. The application frequency should be increased at weekly intervals to once daily, then twice daily, then three times daily and finally four times daily according to individual lesion tolerance. Generally, patients were able to maintain a dosing frequency of two to four times per day. Most responses were seen at dosing frequencies of two times per day and higher. If application site toxicity occurs, the application frequency can be reduced. Should severe irritation occur, application of drug can be temporarily discontinued for a few days until the symptoms subside. - Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry before covering with clothing. Because unaffected skin may become irritated, application of the gel to normal skin surrounding the lesions should be avoided. In addition, do not apply the gel near mucosal surfaces of the body. - A response may be seen as soon as four weeks after initiation of therapy but most patients require longer application. With continued application, further benefit may be attained. The longest onset time for the first response among the responders was 392 days based on the Composite Assessment of Index Lesion Severity in the multicenter study. In clinical trials, Bexarotene was applied for up to 172 weeks. - Bexarotene should be continued as long as the patient is deriving benefit. - Occlusive dressings should not be used with Bexarotene. - Bexarotene is a topical therapy and is not intended for systemic use. - Bexarotene has not been studied in combination with other CTCL therapies. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bexarotene in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bexarotene in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use Safety and effectiveness in pediatric patients have not been established. ### Non–Guideline-Supported Use Safety and effectiveness in pediatric patients have not been established. # Contraindications - Bexarotene 1% is contraindicated in patients with a known hypersensitivity to bexarotene or other components of the product. # Warnings ### Precautions - Bexarotene should be used with caution in patients with a known hypersensitivity to other retinoids. No clinical instances of cross-reactivity have been noted. - Vitamin A Supplementation: In clinical studies, patients were advised to limit vitamin A intake to ≤ 15,000 IU/day. Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to avoid potential additive toxic effects. - Photosensitivity: Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. There were no reports of photosensitivity in patients in the clinical studies. Patients should be advised to minimize exposure to sunlight and artificial ultraviolet light during the use of Bexarotene. - Bexarotene is highly bound (>99%) to plasma proteins. The plasma proteins to which bexarotene binds have not been elucidated, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene binding have not been studied. # Adverse Reactions ## Clinical Trials Experience - The safety of Bexarotene has been assessed in clinical studies of 117 patients with CTCL who received Bexarotene for up to 172 weeks. In the multicenter open-label study, 50 patients with CTCL received Bexarotene for up to 98 weeks. The mean duration of therapy for these 50 patients was 199 days. The most common adverse events reported with an incidence at the application site of at least 10% in patients with CTCL were rash, pruritus, skin disorder, and pain. - Adverse events leading to dose reduction or study drug discontinuation in at least two patients were rash, contact dermatitis, and pruritus. - Of the 49 patients (98%) who experienced any adverse event, most experienced events categorized as mild (9 patients, 18%) or moderate (27 patients, 54%). There were 12 patients (24%) who experienced at least one moderately severe adverse event. The most common moderately severe events were rash (7 patients, 14%) and pruritus (3 patients, 6%). Only one patient (2%) experienced a severe adverse event (rash). - In the patients with CTCL receiving Bexarotene, adverse events reported regardless of relationship to study drug at an incidence of ≥5% are presented in Table 1. - A similar safety profile for Bexarotene was demonstrated in the Phase I-II program. For the 67 patients enrolled in the Phase I-II program, the mean duration of treatment was 436 days (range 12-1203 days). As in the multicenter study, the most common adverse events regardless of relationship to study drug in the Phase I-II program were rash (78%), pain (40%), and pruritus (40%). ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Bexarotene in the drug label. # Drug Interactions - Patients who are applying Bexarotene should not concurrently use products that contain DEET (N,N-diethyl-m-toluamide), a common component of insect repellent products. An animal toxicology study showed increased DEET toxicity when DEET was included as part of the formulation. - No formal studies to evaluate drug interactions with bexarotene have been conducted. Bexarotene oxidative metabolites appear to be formed through cytochrome P450 3A4. - On the basis of the metabolism of bexarotene by cytochrome P450 3A4, concomitant ketoconazole, itraconazole, erythromycin and grapefruit juice could increase bexarotene plasma concentrations. Similarly, based on data that gemfibrozil increases bexarotene concentrations following oral bexarotene administration, concomitant gemfibrozil could increase bexarotene plasma concentrations. However, due to the low systemic exposure to bexarotene after low to moderately intense gel regimens, increases that occur are unlikely to be of sufficient magnitude to result in adverse effects. - No drug interaction data are available on concomitant administration of Bexarotene and other CTCL therapies. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Bexarotene 1% may cause fetal harm when administered to a pregnant woman. - Bexarotene must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking Bexarotene, Bexarotene must be stopped immediately and the woman given appropriate counseling. - Bexarotene caused malformations when administered orally to pregnant rats during days 7-17 of gestation. Developmental abnormalities included incomplete ossification at 4 mg/kg/day and cleft palate, depressed eye bulge/microphthalmia, and small ears at 16 mg/kg/day. At doses greater than 10 mg/kg/day, bexarotene caused developmental mortality. The no-effect oral dose in rats was 1 mg/kg/day. Plasma bexarotene concentrations in patients with CTCL applying Bexarotene 1% were generally less than one hundredth the Cmax associated with dysmorphogenesis in rats, although some patients had Cmax levels that were approximately one eighth the concentration associated with dysmorphogenesis in rats. - Women of child-bearing potential should be advised to avoid becoming pregnant when Bexarotene is used. The possibility that a woman of child-bearing potential is pregnant at the time therapy is instituted should be considered. A negative pregnancy test (e.g., serum beta-human chorionic gonadotropin, beta-HCG) with a sensitivity of at least 50 mIU/L should be obtained within one week prior to Bexarotene therapy, and the pregnancy test must be repeated at monthly intervals while the patient remains on Bexarotene. Effective contraception must be used for one month prior to the initiation of therapy, during therapy and for at least one month following discontinuation of therapy; it is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must use condoms during sexual intercourse while applying Bexarotene and for at least one month after the last dose of drug. Bexarotene therapy should be initiated on the second or third day of a normal menstrual period. No more than a one month supply of Bexarotene should be given to the patient so that the results of pregnancy testing can be assessed and counseling regarding avoidance of pregnancy and birth defects can be reinforced. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bexarotene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bexarotene during labor and delivery. ### Nursing Mothers - It is not known whether bexarotene is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bexarotene, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total patients with CTCL in clinical studies of Bexarotene, 62% were under 65 years and 38% were 65 years or older. No overall differences in safety were observed between patients 65 years of age or older and younger patients, but greater sensitivity of some older individuals to Bexarotene cannot be ruled out. Responses to Bexarotene were observed across all age group decades, without preference for any individual age group decade. ### Gender There is no FDA guidance on the use of Bexarotene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bexarotene with respect to specific racial populations. ### Renal Impairment - No formal studies have been conducted with Bexarotene in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway for bexarotene (99% protein bound, pharmacokinetics may be altered in patients with renal insufficiency. ### Hepatic Impairment - No specific studies have been conducted with Bexarotene in patients with hepatic insufficiency. Because less than 1% of the dose of oral bexarotene is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bexarotene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bexarotene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Bexarotene in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Bexarotene in the drug label. # Overdosage - Systemic toxicity following acute overdosage with topical application of Bexarotene is unlikely because of low systemic plasma levels observed with normal therapeutic doses. There is no specific antidote for overdosage. - There has been no experience with acute overdose of Bexarotene in humans. Any overdose with Bexarotene should be treated with supportive care for the signs and symptoms exhibited by the patient. # Pharmacology There is limited information regarding Bexarotene Pharmacology in the drug label. ## Mechanism of Action - Bexarotene selectively binds and activates retinoid X receptor subtypes (RXRα, RXRβ, RXRγ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. The exact mechanism of action of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) is unknown. ## Structure - Bexarotene 1% contains bexarotene and is intended for topical application only. Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). - The chemical name is 4- benzoic acid, and the structural formula is as follows: - Bexarotene is an off-white to white powder with a molecular weight of 348.48 and a molecular formula of C24H28O2. It is insoluble in water and slightly soluble in vegetable oils and ethanol, USP. - Bexarotene is a clear gelled solution containing 1.0% (w/w) bexarotene in a base of dehydrated alcohol, USP, polyethylene glycol 400, NF, hydroxypropyl cellulose, NF, and butylated hydroxytoluene, NF. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Bexarotene in the drug label. ## Pharmacokinetics - Plasma concentrations of bexarotene were determined during clinical studies in patients with CTCL or following repeated single or multiple-daily dose applications of Bexarotene 1% for up to 132 weeks. Plasma bexarotene concentrations were generally less than 5 ng/mL and did not exceed 55 ng/mL. However, only two patients with very intense dosing regimens (> 40% BSA lesions and QID dosing) were sampled. Plasma bexarotene concentrations and the frequency of detecting quantifiable plasma bexarotene concentrations increased with increasing percent body surface area treated and increasing quantity of Bexarotene applied. The sporadically observed and generally low plasma bexarotene concentrations indicated that, in patients receiving doses of low to moderate intensity, there is a low potential for significant plasma concentrations following repeated application of Bexarotene. Bexarotene is highly bound (>99%) to plasma proteins. The plasma proteins to which bexarotene binds have not been elucidated, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene binding have not been studied . The uptake of bexarotene by organs or tissues has not been evaluated. - Four bexarotene metabolites have been identified in plasma following oral administration of bexarotene: 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. In vitro studies suggest that cytochrome P450 3A4 is the major cytochrome P450 responsible for formation of the oxidative metabolites and that the oxidative metabolites may be glucuronidated. The oxidative metabolites are active in in vitro assays of retinoid receptor activation, but the relative contribution of the parent and any metabolites to the efficacy and safety of Bexarotene is unknown. - The renal elimination of bexarotene and its metabolites was examined in patients with Type 2 diabetes mellitus following oral administration of bexarotene. Neither bexarotene nor its metabolites were excreted in urine in appreciable amounts. - Elderly, Gender, Race: Because of a large number of immeasurable plasma concentrations (< 1 ng/mL), any potential pharmacokinetic differences between Special Populations could not be assessed. - Pediatric: Studies to evaluate bexarotene pharmacokinetics in the pediatric population have not been conducted . - Renal Insufficiency: No formal studies have been conducted with Bexarotene in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of an orally administered dose), but because renal insufficiency can result in significant protein binding changes, pharmacokinetics may be altered in patients with renal insufficiency . - Hepatic Insufficiency: No specific studies have been conducted with Bexarotene in patients with hepatic insufficiency. Because less than 1% of the dose of oral bexarotene is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance . - No formal studies to evaluate drug interactions with bexarotene or Bexarotene have been conducted. Bexarotene oxidative metabolites appear to be formed through cytochrome P450 3A4. Drugs that affect levels or activity of cytochrome P450 3A4 may potentially affect the disposition of bexarotene. Concomitant gemfibrozil was associated with increased bexarotene concentrations following oral administration of bexarotene. ## Nonclinical Toxicology - Long-term studies in animals to assess the carcinogenic potential of bexarotene have not been conducted. Bexarotene was not mutagenic to bacteria (Ames assay) or mammalian cells (mouse lymphoma assay). Bexarotene was not clastogenic in vivo (micronucleus test in mice). No formal fertility studies were conducted with bexarotene. Bexarotene caused testicular degeneration when oral doses of 1.5 mg/kg/day were given to dogs for 91 days. # Clinical Studies - Bexarotene was evaluated for the treatment of patients with early stage (Stage IA-IIA) CTCL in one multicenter, open-label, clinical trial as well as in a Phase I-II program (dose-seeking trials with different response criteria than the multicenter trial). These clinical studies enrolled a total of 117 patients. - In the multicenter, open-label clinical trial, Bexarotene was evaluated for the treatment of patients with early stage CTCL who were refractory to, intolerant to, or reached a response plateau for at least six months on at least two prior therapies. The study was conducted in the U.S., Canada, Europe, and Australia and enrolled a total of 50 patients; 46% of these patients were male, 80% were Caucasian, and the median age was 64 years (range 13 to 85). - Bexarotene was also evaluated for the treatment of patients with CTCL in a U.S. Phase I-II program involving patients with early stage CTCL. This program enrolled a total of 67 patients; 55% of these patients were male, 85% were Caucasian, and the median age was 61 years (range 30 to 87). - In the multicenter, open-label clinical trial, considering prior systemic, irradiation, and topical treatments, patients had been exposed to a median of three prior therapies (range 2-7). All patients failed at least two treatments; the majority (68%) of patients were either refractory to two or more therapies or were refractory to one therapy and intolerant to at least one therapy. - Patients were treated with Bexarotene 1% for a planned 16-week period with an option to continue provided that no unacceptable toxicity was occurring. - Tumor response was assessed in the multicenter study by observation of up to five baseline-defined index lesions using a Composite Assessment of Index Lesion Disease Severity (CA). This endpoint was based on a summation of the grades, for all index lesions, of erythema, scaling, plaque elevation, hypopigmentation or hyperpigmentation, and area of involvement. New cutaneous lesions or tumors and extracutaneous disease manifestations were not considered in response or disease progression assessments. - All tumor responses required confirmation over at least two assessments separated by at least four weeks. A partial response was defined as an improvement of at least 50% in the index lesions. A complete clinical response required complete disappearance of the index lesions, but did not require confirmation by biopsy. - Bexarotene produced an overall response rate of 26% (13/50) with a corresponding exact 95% confidence interval from 14.6% to 40.3% by the Composite Assessment of Index Lesion Severity. For the Stage IA and IB patients, the response rate was 28% (13/47) with a corresponding exact 95% confidence interval from 15.6% to 42.6%. For the Stage II patients the response rate was 0% (0/3). Two percent of patients (1/50) had a clinical complete response. The median time to best response on the Composite Assessment of Index Lesion Severity (n=13) was 85 days (range: 36-154). - The rate of relapse in responding patients by the Composite Assessment of Index Lesion Severity was 23% (3/13) over a median observation period of 149 days (range 56-342). *Fourteen patients developed new lesions in untreated areas (14/50; 28%). Four patients developed clinically abnormal lymph nodes (≥ 1 cm diam) (4/50; 8%). One patient developed a cutaneous tumor (1/50; 2%). - The Phase I-II program (dose-seeking trials with different response criteria than the multicenter trial) was supportive of the multicenter study results. # How Supplied - Bexarotene is supplied in tubes containing 60 g (600 mg active bexarotene). - 60 g tube - NDC 62856-604-22 ## Storage - Store at 25°C (77°F); with excursions permitted to 15°-30°C (59°-86°F) . Avoid exposing to high temperatures and humidity after the tube is opened. Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Bexarotene in the drug label. # Precautions with Alcohol - Alcohol-Bexarotene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Bexarotene Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Bexarotene Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Bexarotene Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Bexarotene is an antineoplastic agent that is FDA approved for the treatment of cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies.. Common adverse reactions include rash, pruritus, skin disorder, and pain, peripheral edema, dry skin, photosensitivity, hypothyroidism, abdominal pain, nausea, asthenia, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Bexarotene 1% is indicated for the topical treatment of cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies. - Bexarotene should be initially applied once every other day for the first week. The application frequency should be increased at weekly intervals to once daily, then twice daily, then three times daily and finally four times daily according to individual lesion tolerance. Generally, patients were able to maintain a dosing frequency of two to four times per day. Most responses were seen at dosing frequencies of two times per day and higher. If application site toxicity occurs, the application frequency can be reduced. Should severe irritation occur, application of drug can be temporarily discontinued for a few days until the symptoms subside. - Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry before covering with clothing. Because unaffected skin may become irritated, application of the gel to normal skin surrounding the lesions should be avoided. In addition, do not apply the gel near mucosal surfaces of the body. - A response may be seen as soon as four weeks after initiation of therapy but most patients require longer application. With continued application, further benefit may be attained. The longest onset time for the first response among the responders was 392 days based on the Composite Assessment of Index Lesion Severity in the multicenter study. In clinical trials, Bexarotene was applied for up to 172 weeks. - Bexarotene should be continued as long as the patient is deriving benefit. - Occlusive dressings should not be used with Bexarotene. - Bexarotene is a topical therapy and is not intended for systemic use. - Bexarotene has not been studied in combination with other CTCL therapies. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bexarotene in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bexarotene in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use Safety and effectiveness in pediatric patients have not been established. ### Non–Guideline-Supported Use Safety and effectiveness in pediatric patients have not been established. # Contraindications - Bexarotene 1% is contraindicated in patients with a known hypersensitivity to bexarotene or other components of the product. # Warnings ### Precautions - Bexarotene should be used with caution in patients with a known hypersensitivity to other retinoids. No clinical instances of cross-reactivity have been noted. - Vitamin A Supplementation: In clinical studies, patients were advised to limit vitamin A intake to ≤ 15,000 IU/day. Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to avoid potential additive toxic effects. - Photosensitivity: Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. There were no reports of photosensitivity in patients in the clinical studies. Patients should be advised to minimize exposure to sunlight and artificial ultraviolet light during the use of Bexarotene. - Bexarotene is highly bound (>99%) to plasma proteins. The plasma proteins to which bexarotene binds have not been elucidated, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene binding have not been studied. # Adverse Reactions ## Clinical Trials Experience - The safety of Bexarotene has been assessed in clinical studies of 117 patients with CTCL who received Bexarotene for up to 172 weeks. In the multicenter open-label study, 50 patients with CTCL received Bexarotene for up to 98 weeks. The mean duration of therapy for these 50 patients was 199 days. The most common adverse events reported with an incidence at the application site of at least 10% in patients with CTCL were rash, pruritus, skin disorder, and pain. - Adverse events leading to dose reduction or study drug discontinuation in at least two patients were rash, contact dermatitis, and pruritus. - Of the 49 patients (98%) who experienced any adverse event, most experienced events categorized as mild (9 patients, 18%) or moderate (27 patients, 54%). There were 12 patients (24%) who experienced at least one moderately severe adverse event. The most common moderately severe events were rash (7 patients, 14%) and pruritus (3 patients, 6%). Only one patient (2%) experienced a severe adverse event (rash). - In the patients with CTCL receiving Bexarotene, adverse events reported regardless of relationship to study drug at an incidence of ≥5% are presented in Table 1. - A similar safety profile for Bexarotene was demonstrated in the Phase I-II program. For the 67 patients enrolled in the Phase I-II program, the mean duration of treatment was 436 days (range 12-1203 days). As in the multicenter study, the most common adverse events regardless of relationship to study drug in the Phase I-II program were rash (78%), pain (40%), and pruritus (40%). ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Bexarotene in the drug label. # Drug Interactions - Patients who are applying Bexarotene should not concurrently use products that contain DEET (N,N-diethyl-m-toluamide), a common component of insect repellent products. An animal toxicology study showed increased DEET toxicity when DEET was included as part of the formulation. - No formal studies to evaluate drug interactions with bexarotene have been conducted. Bexarotene oxidative metabolites appear to be formed through cytochrome P450 3A4. - On the basis of the metabolism of bexarotene by cytochrome P450 3A4, concomitant ketoconazole, itraconazole, erythromycin and grapefruit juice could increase bexarotene plasma concentrations. Similarly, based on data that gemfibrozil increases bexarotene concentrations following oral bexarotene administration, concomitant gemfibrozil could increase bexarotene plasma concentrations. However, due to the low systemic exposure to bexarotene after low to moderately intense gel regimens, increases that occur are unlikely to be of sufficient magnitude to result in adverse effects. - No drug interaction data are available on concomitant administration of Bexarotene and other CTCL therapies. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): X - Bexarotene 1% may cause fetal harm when administered to a pregnant woman. - Bexarotene must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking Bexarotene, Bexarotene must be stopped immediately and the woman given appropriate counseling. - Bexarotene caused malformations when administered orally to pregnant rats during days 7-17 of gestation. Developmental abnormalities included incomplete ossification at 4 mg/kg/day and cleft palate, depressed eye bulge/microphthalmia, and small ears at 16 mg/kg/day. At doses greater than 10 mg/kg/day, bexarotene caused developmental mortality. The no-effect oral dose in rats was 1 mg/kg/day. Plasma bexarotene concentrations in patients with CTCL applying Bexarotene 1% were generally less than one hundredth the Cmax associated with dysmorphogenesis in rats, although some patients had Cmax levels that were approximately one eighth the concentration associated with dysmorphogenesis in rats. - Women of child-bearing potential should be advised to avoid becoming pregnant when Bexarotene is used. The possibility that a woman of child-bearing potential is pregnant at the time therapy is instituted should be considered. A negative pregnancy test (e.g., serum beta-human chorionic gonadotropin, beta-HCG) with a sensitivity of at least 50 mIU/L should be obtained within one week prior to Bexarotene therapy, and the pregnancy test must be repeated at monthly intervals while the patient remains on Bexarotene. Effective contraception must be used for one month prior to the initiation of therapy, during therapy and for at least one month following discontinuation of therapy; it is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must use condoms during sexual intercourse while applying Bexarotene and for at least one month after the last dose of drug. Bexarotene therapy should be initiated on the second or third day of a normal menstrual period. No more than a one month supply of Bexarotene should be given to the patient so that the results of pregnancy testing can be assessed and counseling regarding avoidance of pregnancy and birth defects can be reinforced. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bexarotene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bexarotene during labor and delivery. ### Nursing Mothers - It is not known whether bexarotene is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bexarotene, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - Of the total patients with CTCL in clinical studies of Bexarotene, 62% were under 65 years and 38% were 65 years or older. No overall differences in safety were observed between patients 65 years of age or older and younger patients, but greater sensitivity of some older individuals to Bexarotene cannot be ruled out. Responses to Bexarotene were observed across all age group decades, without preference for any individual age group decade. ### Gender There is no FDA guidance on the use of Bexarotene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bexarotene with respect to specific racial populations. ### Renal Impairment - No formal studies have been conducted with Bexarotene in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway for bexarotene (<1% of an orally administered dose), but because renal insufficiency can result in significant protein binding changes, and bexarotene is >99% protein bound, pharmacokinetics may be altered in patients with renal insufficiency. ### Hepatic Impairment - No specific studies have been conducted with Bexarotene in patients with hepatic insufficiency. Because less than 1% of the dose of oral bexarotene is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bexarotene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bexarotene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Bexarotene in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Bexarotene in the drug label. # Overdosage - Systemic toxicity following acute overdosage with topical application of Bexarotene is unlikely because of low systemic plasma levels observed with normal therapeutic doses. There is no specific antidote for overdosage. - There has been no experience with acute overdose of Bexarotene in humans. Any overdose with Bexarotene should be treated with supportive care for the signs and symptoms exhibited by the patient. # Pharmacology There is limited information regarding Bexarotene Pharmacology in the drug label. ## Mechanism of Action - Bexarotene selectively binds and activates retinoid X receptor subtypes (RXRα, RXRβ, RXRγ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. The exact mechanism of action of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) is unknown. ## Structure - Bexarotene 1% contains bexarotene and is intended for topical application only. Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). - The chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl] benzoic acid, and the structural formula is as follows: - Bexarotene is an off-white to white powder with a molecular weight of 348.48 and a molecular formula of C24H28O2. It is insoluble in water and slightly soluble in vegetable oils and ethanol, USP. - Bexarotene is a clear gelled solution containing 1.0% (w/w) bexarotene in a base of dehydrated alcohol, USP, polyethylene glycol 400, NF, hydroxypropyl cellulose, NF, and butylated hydroxytoluene, NF. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Bexarotene in the drug label. ## Pharmacokinetics - Plasma concentrations of bexarotene were determined during clinical studies in patients with CTCL or following repeated single or multiple-daily dose applications of Bexarotene 1% for up to 132 weeks. Plasma bexarotene concentrations were generally less than 5 ng/mL and did not exceed 55 ng/mL. However, only two patients with very intense dosing regimens (> 40% BSA lesions and QID dosing) were sampled. Plasma bexarotene concentrations and the frequency of detecting quantifiable plasma bexarotene concentrations increased with increasing percent body surface area treated and increasing quantity of Bexarotene applied. The sporadically observed and generally low plasma bexarotene concentrations indicated that, in patients receiving doses of low to moderate intensity, there is a low potential for significant plasma concentrations following repeated application of Bexarotene. Bexarotene is highly bound (>99%) to plasma proteins. The plasma proteins to which bexarotene binds have not been elucidated, and the ability of bexarotene to displace drugs bound to plasma proteins and the ability of drugs to displace bexarotene binding have not been studied . The uptake of bexarotene by organs or tissues has not been evaluated. - Four bexarotene metabolites have been identified in plasma following oral administration of bexarotene: 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. In vitro studies suggest that cytochrome P450 3A4 is the major cytochrome P450 responsible for formation of the oxidative metabolites and that the oxidative metabolites may be glucuronidated. The oxidative metabolites are active in in vitro assays of retinoid receptor activation, but the relative contribution of the parent and any metabolites to the efficacy and safety of Bexarotene is unknown. - The renal elimination of bexarotene and its metabolites was examined in patients with Type 2 diabetes mellitus following oral administration of bexarotene. Neither bexarotene nor its metabolites were excreted in urine in appreciable amounts. - Elderly, Gender, Race: Because of a large number of immeasurable plasma concentrations (< 1 ng/mL), any potential pharmacokinetic differences between Special Populations could not be assessed. - Pediatric: Studies to evaluate bexarotene pharmacokinetics in the pediatric population have not been conducted . - Renal Insufficiency: No formal studies have been conducted with Bexarotene in patients with renal insufficiency. Urinary elimination of bexarotene and its known metabolites is a minor excretory pathway (<1% of an orally administered dose), but because renal insufficiency can result in significant protein binding changes, pharmacokinetics may be altered in patients with renal insufficiency . - Hepatic Insufficiency: No specific studies have been conducted with Bexarotene in patients with hepatic insufficiency. Because less than 1% of the dose of oral bexarotene is excreted in the urine unchanged and there is in vitro evidence of extensive hepatic contribution to bexarotene elimination, hepatic impairment would be expected to lead to greatly decreased clearance . - No formal studies to evaluate drug interactions with bexarotene or Bexarotene have been conducted. Bexarotene oxidative metabolites appear to be formed through cytochrome P450 3A4. Drugs that affect levels or activity of cytochrome P450 3A4 may potentially affect the disposition of bexarotene. Concomitant gemfibrozil was associated with increased bexarotene concentrations following oral administration of bexarotene. ## Nonclinical Toxicology - Long-term studies in animals to assess the carcinogenic potential of bexarotene have not been conducted. Bexarotene was not mutagenic to bacteria (Ames assay) or mammalian cells (mouse lymphoma assay). Bexarotene was not clastogenic in vivo (micronucleus test in mice). No formal fertility studies were conducted with bexarotene. Bexarotene caused testicular degeneration when oral doses of 1.5 mg/kg/day were given to dogs for 91 days. # Clinical Studies - Bexarotene was evaluated for the treatment of patients with early stage (Stage IA-IIA) CTCL in one multicenter, open-label, clinical trial as well as in a Phase I-II program (dose-seeking trials with different response criteria than the multicenter trial). These clinical studies enrolled a total of 117 patients. - In the multicenter, open-label clinical trial, Bexarotene was evaluated for the treatment of patients with early stage CTCL who were refractory to, intolerant to, or reached a response plateau for at least six months on at least two prior therapies. The study was conducted in the U.S., Canada, Europe, and Australia and enrolled a total of 50 patients; 46% of these patients were male, 80% were Caucasian, and the median age was 64 years (range 13 to 85). - Bexarotene was also evaluated for the treatment of patients with CTCL in a U.S. Phase I-II program involving patients with early stage CTCL. This program enrolled a total of 67 patients; 55% of these patients were male, 85% were Caucasian, and the median age was 61 years (range 30 to 87). - In the multicenter, open-label clinical trial, considering prior systemic, irradiation, and topical treatments, patients had been exposed to a median of three prior therapies (range 2-7). All patients failed at least two treatments; the majority (68%) of patients were either refractory to two or more therapies or were refractory to one therapy and intolerant to at least one therapy. - Patients were treated with Bexarotene 1% for a planned 16-week period with an option to continue provided that no unacceptable toxicity was occurring. - Tumor response was assessed in the multicenter study by observation of up to five baseline-defined index lesions using a Composite Assessment of Index Lesion Disease Severity (CA). This endpoint was based on a summation of the grades, for all index lesions, of erythema, scaling, plaque elevation, hypopigmentation or hyperpigmentation, and area of involvement. New cutaneous lesions or tumors and extracutaneous disease manifestations were not considered in response or disease progression assessments. - All tumor responses required confirmation over at least two assessments separated by at least four weeks. A partial response was defined as an improvement of at least 50% in the index lesions. A complete clinical response required complete disappearance of the index lesions, but did not require confirmation by biopsy. - Bexarotene produced an overall response rate of 26% (13/50) with a corresponding exact 95% confidence interval from 14.6% to 40.3% by the Composite Assessment of Index Lesion Severity. For the Stage IA and IB patients, the response rate was 28% (13/47) with a corresponding exact 95% confidence interval from 15.6% to 42.6%. For the Stage II patients the response rate was 0% (0/3). Two percent of patients (1/50) had a clinical complete response. The median time to best response on the Composite Assessment of Index Lesion Severity (n=13) was 85 days (range: 36-154). - The rate of relapse in responding patients by the Composite Assessment of Index Lesion Severity was 23% (3/13) over a median observation period of 149 days (range 56-342). *Fourteen patients developed new lesions in untreated areas (14/50; 28%). Four patients developed clinically abnormal lymph nodes (≥ 1 cm diam) (4/50; 8%). One patient developed a cutaneous tumor (1/50; 2%). - The Phase I-II program (dose-seeking trials with different response criteria than the multicenter trial) was supportive of the multicenter study results. # How Supplied - Bexarotene is supplied in tubes containing 60 g (600 mg active bexarotene). - 60 g tube - NDC 62856-604-22 ## Storage - Store at 25°C (77°F); with excursions permitted to 15°-30°C (59°-86°F) [see USP]. Avoid exposing to high temperatures and humidity after the tube is opened. Protect from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Bexarotene in the drug label. # Precautions with Alcohol - Alcohol-Bexarotene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Bexarotene Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Bexarotene Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Bexarotene
6b9a38a06439a4b29630577714c9edd30dc4f4bd	wikidoc	Valdecoxib	Valdecoxib # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Valdecoxib is a Cyclooxygenase-2 Inhibitor that is FDA approved for the treatment of osteoarthritis, adult rheumatoid arthritis and primary dysmenorrhea. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Abdominal pain, Diarrhea, Flatulence, Indigestion, Nausea, Dizziness, Headache, Rash, Hypertension, Peripheral edema , Backache, Myalgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - For relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis. - For the treatment of primary dysmenorrhea ### Dosage - The recommended dose of BEXTRA Tablets for the relief of the signs and symptoms of arthritis is 10 mg once daily. - The recommended dose of BEXTRA Tablets for treatment of primary dysmenorrhea is 20 mg twice daily, as needed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Valdecoxib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Valdecoxib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Valdecoxib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Valdecoxib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Valdecoxib in pediatric patients. # Contraindications - BEXTRA should not be given to patients who have demonstrated allergic-type reactions to sulfonamides. - BEXTRA Tablets are contraindicated in patients with known hypersensitivity to valdecoxib. BEXTRA should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs are possible in such patients. - BEXTRA is contraindicated for the treatment of post-operative pain immediately following coronary artery bypass graft (CABG) surgery and should not be used in this setting. # Warnings - Serious gastrointestinal toxicity such as bleeding, ulceration and perforation of the stomach, small intestine or large intestine can occur at any time with or without warning symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor gastrointestinal problems such as dyspepsia are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding even in the absence of previous GI tract symptoms. Patients should be informed about the signs and symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation caused by NSAIDs appear to occur in approximately 1% of patients treated for 3 to 6 months and 2–4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. - NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. - Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status. - Valdecoxib contains a sulfonamide moiety and patients with a known history of a sulfonamide allergy may be at a greater risk of skin reactions. Patients without a history of sulfonamide allergy may also be at risk for serious skin reactions. - Serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported through postmarketing surveillance in patients receiving BEXTRA . Fatalities due to Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Patients appear to be at higher risk for these events early in the course of therapy, with the onset of the event occurring in the majority of cases within the first two weeks of treatment. BEXTRA should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Serious skin reactions have been reported with other COX-2 inhibitors during postmarketing experience. The reported rate of these events appears to be greater for BEXTRA as compared to other COX-2 agents. - In postmarketing experience, cases of hypersensitivity reactions (anaphylactic reactions and angioedema) have been reported in patients receiving BEXTRA. These cases have occurred in patients with and without a history of allergic-type reactions to sulfonamides. BEXTRA should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. - Emergency help should be sought in cases where an anaphylactoid reaction occurs. - Patients treated with BEXTRA for pain following coronary artery bypass graft surgery have a higher risk for cardiovascular/thromboembolic events, deep surgical infections or sternal wound complications. BEXTRA is therefore contraindicated for the treatment of postoperative pain following CABG surgery. - No information is available regarding the safe use of BEXTRA Tablets in patients with advanced kidney disease. Therefore, treatment with BEXTRA is not recommended in these patients. If therapy with BEXTRA must be initiated, close monitoring of the patient's kidney function is advisable. - In late pregnancy, BEXTRA should be avoided because it may cause premature closure of the ductus arteriosus. ### Precautions - BEXTRA Tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. - The pharmacological activity of valdecoxib in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. - Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may remain transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs. In controlled clinical trials of valdecoxib, the incidence of borderline (defined as 1.2- to 3.0-fold) elevations of liver tests was 8.0% for valdecoxib and 8.4% for placebo, while approximately 0.3% of patients taking valdecoxib, and 0.2% of patients taking placebo, had notable (defined as greater than 3-fold) elevations of ALT or AST. - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with BEXTRA. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), BEXTRA should be discontinued. - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and Angiotensin Converting Enzyme (ACE) inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. - Caution should be used when initiating treatment with BEXTRA in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with BEXTRA. Caution is also recommended in patients with preexisting kidney disease. - Anemia is sometimes seen in patients receiving BEXTRA. Patients on long-term treatment with BEXTRA should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. - BEXTRA does not generally affect platelet counts, prothrombin time (PT), or activated partial thromboplastin time (APTT), and does not appear to inhibit platelet aggregation at indicated dosages. - Fluid retention and edema have been observed in some patients taking BEXTRA. Therefore, BEXTRA should be used with caution in patients with fluid retention, hypertension, or heart failure. - Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, BEXTRA should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. - Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. # Adverse Reactions ## Clinical Trials Experience - Of the patients treated with BEXTRA Tablets in controlled arthritis trials, 2665 were patients with OA, and 2684 were patients with RA. More than 4000 patients have received a chronic total daily dose of BEXTRA 10 mg or more. More than 2800 patients have received BEXTRA 10 mg/day, or more, for at least 6 months and 988 of these have received BEXTRA for at least 1 year. - Table 4 lists all adverse events, regardless of causality, that occurred in ≥2.0% of patients receiving BEXTRA 10 and 20 mg/day in studies of three months or longer from 7 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. - In these placebo- and active-controlled clinical trials, the discontinuation rate due to adverse events was 7.5% for arthritis patients receiving valdecoxib 10 mg daily, 7.9% for arthritis patients receiving valdecoxib 20 mg daily and 6.0%for patients receiving placebo. - In the seven controlled OA and RA studies, the following adverse events occurred in 0.1–1.9% of patients treated with BEXTRA 10–20 mg daily, regardless of causality. - Cellulitis, dermatitis contact - Aggravated hypertension, aneurysm, angina pectoris, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disorder, heart murmur, hypotension - Cerebrovascular disorder, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, tremor, twitching, vertigo - Goiter - Amenorrhea, dysmenorrhea, leukorrhea, mastitis, menstrual disorder, menorrhagia, menstrual bloating, vaginal hemorrhage - Abnormal stools, constipation, diverticulosis, dry mouth, duodenal ulcer, duodenitis, eructation, esophagitis, fecal incontinence, gastric ulcer, gastritis, gastroenteritis, gastroesophageal reflux, hematemesis, hematochezia, hemorrhoids, hemorrhoids bleeding, hiatal hernia, melena, stomatitis, stool frequency increased, tenesmus, tooth disorder, vomiting - Allergy aggravated, allergic reaction, asthenia, chest pain, chills, cyst NOS, generalized edema, face edema, fatigue, fever, hot flushes, halitosis, malaise, pain, periorbital swelling, peripheral pain - Ear abnormality, earache, tinnitus - Bradycardia, palpitation, tachycardia - Anemia - abnormal Hepatic function , hepatitis, ALT increased, AST increased - Impotence, prostatic disorder - Alkaline phosphatase increased, BUN increased, CPK increased, creatinine increased, diabetes mellitus, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia, hypocalcemia, hypokalemia, LDH increased, thirst increased, weight loss, weight gain, xerophthalmia - Arthralgia, fracture accidental, neck stiffness, osteoporosis, synovitis, tendonitis - Breast neoplasm, lipoma, malignant ovarian cyst - Ecchymosis, epistaxis, hematoma NOS, thrombocytopenia - Anorexia, anxiety, appetite increased, confusion, depression, depression aggravated, insomnia, nervousness, morbid dreaming, somnolence - Herpes simplex, herpes zoster, fungal infection, soft tissue infection, viral infection, moniliasis, moniliasis genital, otitis media - Abnormal breath sounds, bronchitis, bronchospasm, coughing, dyspnea, emphysema, laryngitis, pneumonia, pharyngitis, pleurisy, rhinitis - Acne, alopecia, dermatitis, fungal dermatitis , eczema, photosensitivity allergic reaction, pruritus, erythematous rash, maculopapular rash, psoriaform rash, skin dry, skin hypertrophy, skin ulceration, increased sweating, urticaria - Taste perversion - Albuminuria, cystitis, dysuria, hematuria, micturition frequency increased, pyuria, urinary incontinence, urinary tract infection - intermittent Claudication , acquired hemangioma , varicose vein - Blurred vision, cataract, conjunctival hemorrhage, conjunctivitis, eye pain, keratitis, abnormal vision - Eosinophilia, leukopenia, leukocytosis, lymphadenopathy, lymphangitis, lymphopenia - Other serious adverse events that were reported rarely (estimated <0.1%) in clinical trials, regardless of causality, in patients taking BEXTRA: - Hypertensive encephalopathy, vasospasm - Abnormal ECG, aortic stenosis, atrial fibrillation, carotid stenosis, coronary thrombosis, heart block, heart valve disorders, mitral insufficiency, myocardial infarction, myocardial ischemia, pericarditis, syncope, thrombophlebitis, unstable angina, ventricular fibrillation - Convulsions - Hyperparathyroidism - Cervical dysplasia - Appendicitis, colitis with bleeding, dysphagia, esophageal perforation, gastrointestinal bleeding, ileus, intestinal obstruction, peritonitis - Lymphoma-like disorder, pancytopenia - Cholelithiasis - Dehydration - Pathological fracture, osteomyelitis - Benign brain neoplasm, bladder carcinoma, carcinoma, gastric carcinoma, prostate carcinoma, pulmonary carcinoma - Embolism, pulmonary embolism, thrombosis - Manic reaction, psychosis - Acute renal failure - Sepsis - Apnea, pleural effusion, pulmonary edema, pulmonary fibrosis, pulmonary infarction, pulmonary hemorrhage, respiratory insufficiency - Basal cell carcinoma, malignant melanoma - Pyelonephritis, renal calculus - Retinal detachment ## Postmarketing Experience - The following reactions have been identified during postmarketing use of BEXTRA. These reactions have been chosen for inclusion either due to their seriousness, reporting frequency, possible causal relationship to BEXTRA, or a combination of these factors. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - General: Hypersensitivity reactions (including anaphylactic reactions and angioedema) - Gastrointestinal: Pancreatitis - Skin and appendages: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis # Drug Interactions - The drug interaction studies with valdecoxib were performed both with valdecoxib and a rapidly hydrolyzed intravenous prodrug form. The results from trials using the intravenous prodrug are reported in this section as they relate to the role of valdecoxib in drug interactions. - In humans, valdecoxib metabolism is predominantly mediated via CYP 3A4 and 2C9 with glucuronidation being a further (20%) route of metabolism. In vitro studies indicate that valdecoxib is a moderate inhibitor of CYP 2C19 (IC50 = 6 µg/mL or 19 µM) and 2C9 (IC50 = 13 µg/mL or 41 µM), and a weak inhibitor of CYP 2D6 (IC50 = 31 µg/mL or 100 µM) and 3A4 (IC50 = 44 µg/mL or 141 µM). - Concomitant administration of aspirin with valdecoxib may result in an increased risk of GI ulceration and complications compared to valdecoxib alone. Because of its lack of anti-platelet effect valdecoxib is not a substitute for aspirin for cardiovascular prophylaxis. - In a parallel group drug interaction study comparing the intravenous prodrug form of valdecoxib at 40 mg BID (n=10) vs placebo (n=9), valdecoxib had no effect on in vitro aspirin-mediated inhibition of arachidonate- or collagen-stimulated platelet aggregation. - Valdecoxib 10 mg BID did not show a significant effect on the plasma exposure or renal clearance of methotrexate. - Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking BEXTRA concomitantly with ACE-inhibitors. - Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. - Steady state plasma exposure (AUC) of valdecoxib (40 mg BID for 12 days) was decreased by 27% when coadministered with multiple doses (300 mg QD for 12 days) of phenytoin (a CYP 3A4 inducer). Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration. Valdecoxib did not have a statistically significant effect on the pharmacokinetics of phenytoin (a CYP 2C9 and CYP 2C19 substrate). - Drug interaction studies with other anticonvulsants have not been conducted. Routine monitoring should be performed when therapy with BEXTRA is either initiated or discontinued in patients on anticonvulsant therapy. - Dextromethorphan is primarily metabolized by CYP 2D6 and to a lesser extent by 3A4. Coadministration with valdecoxib (40 mg BID for 7 days) resulted in a significant increase in dextromethorphan plasma levels suggesting that, at these doses, valdecoxib is a weak inhibitor of 2D6. Even so, dextromethorphan plasma concentrations in the presence of high doses of valdecoxib were almost 5-fold lower than those seen in CYP 2D6 poor metabolizers suggesting that dose adjustment is not necessary. - Valdecoxib 40 mg BID for 7 days produced significant decreases in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone. Lithium serum concentrations should be monitored closely when initiating or changing therapy with BEXTRA in patients receiving lithium. Lithium carbonate (450 mg BID for 7 days) had no effect on valdecoxib pharmacokinetics. - The effect of valdecoxib on the anticoagulant effect of warfarin (1–8 mg/day) was studied in healthy subjects by coadministration of BEXTRA 40 mg BID for 7 days. Valdecoxib caused a statistically significant increase in plasma exposures of R-warfarin and S-warfarin (12% and 15%, respectively), and in the pharmacodynamic effects (prothrombin time, measured as INR) of warfarin. While mean INR values were only slightly increased with coadministration of valdecoxib, the day-to-day variability in individual INR values was increased. Anticoagulant therapy should be monitored, particularly during the first few weeks, after initiating therapy with BEXTRA in patients receiving warfarin or similar agents. - Ketoconazole and fluconazole are predominantly CYP 3A4 and 2C9 inhibitors, respectively. Concomitant single dose administration of valdecoxib 20 mg with multiple doses of ketoconazole and fluconazole produced a significant increase in exposure of valdecoxib. Plasma exposure (AUC) to valdecoxib was increased 62% when coadministered with fluconazole and 38% when coadministered with ketoconazole. - Glyburide is a CYP 2C9 substrate. Coadministration of valdecoxib (10 mg BID for 7 days) with glyburide (5 mg QD or 10 mg BID) did not affect the pharmacokinetics (exposure) of glyburide. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2–7)) with glyburide (5 mg QD) did not affect either the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of glyburide. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2–7)) with glyburide (10 mg glyburide BID) resulted in 21% increase in glyburide AUC(0–12hr) and a 16% increase in glyburide Cmax leading to a 16%decrease in glucose AUC(0–24hr). Insulin parameters were not affected. Because changes in glucose concentrations with valdecoxib coadministration were within the normal variability and individual glucose concentrations were above or near 70 mg/dL, dose adjustment for glyburide (5 mg QD and 10 mg BID) with valdecoxib coadministration (up to 40 mg QD) is not indicated. Coadministration of glyburide with doses higher than 40 mg valdecoxib (e.g., 40 mg BID) has not been studied. - Omeprazole is a CYP 3A4 substrate and CYP 2C19 substrate and inhibitor. Valdecoxib steady state plasma concentrations (40 mg BID) were not affected significantly with multiple doses of omeprazole (40 mg QD). Coadministration with valdecoxib increased exposure of omeprazole (AUC) by 46%. Drugs whose absorption is sensitive to pH may be negatively impacted by concomitant administration of omeprazole and valdecoxib. However, because higher doses (up to 360 mg QD) of omeprazole are tolerated in Zollinger-Ellison (ZE) patients, no dose adjustment for omeprazole is recommended at current doses. Coadministration of valdecoxib with doses higher than 40 mg QD omeprazole has not been studied. - Valdecoxib (40 mg BID) did not induce the metabolism of the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg combination, Ortho-Novum 1/35®). Coadministration of valdecoxib and Ortho-Novum 1/35® increased the exposure of norethindrone and ethinyl estradiol by 20% and 34%, respectively. Although there is little risk for loss of contraceptive efficacy, the clinical significance of these increased exposures in terms of safety is not known. These increased exposures of norethindrone and ethinyl estradiol should be taken into consideration when selecting an oral contraceptive for women taking valdecoxib. - Diazepam (Valium®) is a CYP 3A4 and CYP 2C19 substrate. Plasma exposure of diazepam (10 mg BID) was increased by 28% following administration of valdecoxib (40 mg BID) for 12 days, while plasma exposure of valdecoxib (40 mg BID) was not substantially increased following administration of diazepam (10 mg BID) for 12 days. Although the magnitude of changes in diazepam plasma exposure when coadministered with valdecoxib were not sufficient to warrant dosage adjustments, patients may experience enhanced sedative side effects caused by increased exposure of diazepam under this circumstance. Patients should be cautioned against engaging in hazardous activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - The incidence of fetuses with skeletal anomalies such as semi-bipartite thoracic vertebra centra and fused sternebrae was slightly higher in rabbits at an oral dose of 40 mg/kg/day (equivalent to approximately 72-fold human exposures at 20 mg QD as measured by the AUC(0–24hr)) throughout organogenesis. Valdecoxib was not teratogenic in rabbits up to an oral dose of 10 mg/kg/day (equivalent to approximately 8-fold human exposures at 20 mg QD as measured by the AUC(0–24hr)). - Valdecoxib was not teratogenic in rats up to an oral dose of 10 mg/kg/day (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)). There are no studies in pregnant women. However, valdecoxib crosses the placenta in rats and rabbits. BEXTRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Valdecoxib caused increased pre- and post-implantation loss with reduced live fetuses at oral doses ≥10 mg/kg/day (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) in rats and an oral dose of 40 mg/kg/day (equivalent to approximately 72-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) in rabbits throughout organogenesis. In addition, reduced neonatal survival and decreased neonatal body weight when rats were treated with valdecoxib at oral doses ≥6 mg/kg/day (equivalent to approximately 7-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) throughout organogenesis and lactation period. No studies have been conducted to evaluate the effect of valdecoxib on the closure of the ductus arteriosus in humans. Therefore, as with other drugs known to inhibit prostaglandin synthesis, use of BEXTRA during the third trimester of pregnancy should be avoided. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valdecoxib in women who are pregnant. ### Labor and Delivery - Valdecoxib produced no evidence of delayed labor or parturition at oral doses up to 10 mg/kg/day in rats (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)). The effects of BEXTRA on labor and delivery in pregnant women are unknown. ### Nursing Mothers - Valdecoxib and its active metabolite are excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse reactions in nursing infants from BEXTRA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and the importance of nursing to the infant. ### Pediatric Use - Safety and effectiveness of BEXTRA in pediatric patients below the age of 18 years have not been evaluated. ### Geriatic Use - Of the patients who received BEXTRA in arthritis clinical trials of three months duration, or greater, approximately 2100 were 65 years of age or older, including 570 patients who were 75 years or older. No overall differences in effectiveness were observed between these patients and younger patients. ### Gender There is no FDA guidance on the use of Valdecoxib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Valdecoxib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Valdecoxib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Valdecoxib in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Valdecoxib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Valdecoxib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - If therapy with BEXTRA must be initiated, close monitoring of the patient's kidney function is advisable - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with BEXTRA. - Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. - Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration. - Lithium serum concentrations should be monitored closely when initiating or changing therapy with BEXTRA in patients receiving lithium. - Anticoagulant therapy should be monitored, particularly during the first few weeks, after initiating therapy with BEXTRA in patients receiving warfarin or similar agents. # IV Compatibility There is limited information regarding IV Compatibility of Valdecoxib in the drug label. # Overdosage - Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. - Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. - Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Hemodialysis removed only about 2% of administered valdecoxib from the systemic circulation of 8 patients with end-stage renal disease and, based on its degree of plasma protein binding (>98%), dialysis is unlikely to be useful in overdose. Forced diuresis, alkalinization of urine, or hemoperfusion also may not be useful due to high protein binding. # Pharmacology ## Mechanism of Action - Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties in animal models. The mechanism of action is believed to be due to inhibition of prostaglandin synthesis primarily through inhibition of cyclooxygenase-2 (COX-2). At therapeutic plasma concentrations in humans valdecoxib does not inhibit cyclooxygenase-1 (COX-1). ## Structure - Valdecoxib is chemically designated as 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide and is a diaryl substituted isoxazole. It has the following chemical structure: - The empirical formula for valdecoxib is C16H14N2O3S, and the molecular weight is 314.36. Valdecoxib is a white crystalline powder that is relatively insoluble in water (10 µg/mL) at 25°C and pH 7.0, soluble in methanol and ethanol, and freely soluble in organic solvents and alkaline (pH=12) aqueous solutions. - BEXTRA Tablets for oral administration contain either 10 mg or 20 mg of valdecoxib. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol, polysorbate 80, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Valdecoxib in the drug label. ## Pharmacokinetics - Valdecoxib achieves maximal plasma concentrations in approximately 3 hours. The absolute bioavailability of valdecoxib is 83% following oral administration of BEXTRA compared to intravenous infusion of valdecoxib. - Dose proportionality was demonstrated after single doses (1–400 mg) of valdecoxib. With multiple doses (up to 100 mg/day for 14 days), valdecoxib exposure as measured by the AUC, increases in a more than proportional manner at doses above 10 mg BID. Steady state plasma concentrations of valdecoxib are achieved by day 4. - The steady state pharmacokinetic parameters of valdecoxib in healthy male subjects are shown in Table 1. - No clinically significant age or gender differences were seen in pharmacokinetic parameters that would require dosage adjustments. - Effect of Food and Antacid - BEXTRA can be taken with or without food. Food had no significant effect on either the peak plasma concentration (Cmax) or extent of absorption (AUC) of valdecoxib when BEXTRA was taken with a high fat meal. The time to peak plasma concentration (Tmax), however, was delayed by 1–2 hours. Administration of BEXTRA with antacid (aluminum/magnesium hydroxide) had no significant effect on either the rate or extent of absorption of valdecoxib. - Plasma protein binding for valdecoxib is about 98% over the concentration range (21–2384 ng/mL). Steady state apparent volume of distribution (Vss/F) of valdecoxib is approximately 86 L after oral administration. Valdecoxib and its active metabolite preferentially partition into erythrocytes with a blood to plasma concentration ratio of about 2.5:1. This ratio remains approximately constant with time and therapeutic blood concentrations. - In humans, valdecoxib undergoes extensive hepatic metabolism involving both P450 isoenzymes (3A4 and 2C9) and non-P450 dependent pathways (i.e., glucuronidation). Concomitant administration of BEXTRA with known CYP 3A4 and 2C9 inhibitors (e.g., fluconazole and ketoconazole) can result in increased plasma exposure of valdecoxib. - One active metabolite of valdecoxib has been identified in human plasma at approximately 10% the concentration of valdecoxib. This metabolite, which is a less potent COX-2 specific inhibitor than the parent, also undergoes extensive metabolism and constitutes less than 2% of the valdecoxib dose excreted in the urine and feces. Due to its low concentration in the systemic circulation, it is not likely to contribute significantly to the efficacy profile of BEXTRA. - Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. The apparent oral clearance (CL/F) of valdecoxib is about 6 L/hr. The mean elimination half-life (T1/2) ranges from 8–11 hours, and increases with age. - In elderly subjects (> 65 years), weight-adjusted steady state plasma concentrations (AUC(0–12hr)) are about 30% higher than in young subjects. No dose adjustment is needed based on age. - BEXTRA has not been investigated in pediatric patients below 18 years of age. - Pharmacokinetic differences due to race have not been identified in clinical and pharmacokinetic studies conducted to date. - Valdecoxib plasma concentrations are significantly increased (130%) in patients with moderate (Child-Pugh Class B) hepatic impairment. In clinical trials, doses of BEXTRA above those recommended have been associated with fluid retention. Hence, treatment with BEXTRA should be initiated with caution in patients with mild to moderate hepatic impairment and fluid retention. The use of BEXTRA in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. - The pharmacokinetics of valdecoxib have been studied in patients with varying degrees of renal impairment. Because renal elimination of valdecoxib is not important to its disposition, no clinically significant changes in valdecoxib clearance were found even in patients with severe renal impairment or in patients undergoing renal dialysis. In patients undergoing hemodialysis the plasma clearance (CL/F) of valdecoxib was similar to the CL/F found in healthy elderly subjects (CL/F about 6 to 7 L/hr.) with normal renal function (based on creatinine clearance). - NSAIDs have been associated with worsening renal function and use in advanced renal disease is not recommended (see PRECAUTIONS — RENAL EFFECTS). - For quantitative information on the following drug interaction studies, see PRECAUTIONS — DRUG INTERACTIONS. - Valdecoxib undergoes both P450 (CYP) dependent and non-P450 dependent (glucuronidation) metabolism. In vitro studies indicate that valdecoxib is not a significant inhibitor of CYP 1A2, 3A4, or 2D6 and is a weak inhibitor of CYP 2C9 and a weak to moderate inhibitor of CYP 2C19 at therapeutic concentrations. The P450-mediated metabolic pathway of valdecoxib predominantly involves the 3A4 and 2C9 isozymes. Using prototype inhibitors and substrates of these isozymes, the following results were obtained. Coadministration of a known inhibitor of CYP 2C9/3A4 (fluconazole) and a CYP 3A4 inhibitor (ketoconazole) enhanced the total plasma exposure (AUC) of valdecoxib. Coadministration of valdecoxib with a CYP 3A4 inducer (phenytoin) decreased total plasma exposure (AUC) of valdecoxib. - Coadministration of valdecoxib with warfarin (a CYP 2C9 substrate) caused a small, but statistically significant increase in plasma exposures of R-warfarin and S-warfarin, and also in the pharmacodynamic effects (International Normalized Ratio-INR) of warfarin. - Coadministration of valdecoxib with diazepam (a CYP 2C19/3A4 substrate) resulted in increased exposure of diazepam, but not its major metabolite, desmethyldiazepam. - Coadministration of valdecoxib with glyburide (a CYP 2C9 substrate) (40 mg valdecoxib QD with 10 mg glyburide BID) resulted in increased exposure of glyburide. - Coadministration of valdecoxib with an oral contraceptive, 1 mg norethindrone/0.035 mg ethinyl estradiol (CYP 3A4 substrates), resulted in increased exposure of both norethindrone and ethinyl estradiol. - Coadministration of valdecoxib with omeprazole (a CYP 3A4/2C19 substrate) caused an increase in omeprazole exposure. - Coadministration of valdecoxib with dextromethorphan (a CYP 2D6/3A4 substrate) resulted in an increase in dextromethorphan plasma levels above those seen in subjects with normal levels of CYP 2D6. Even so these levels were almost 5-fold lower than those seen in CYP 2D6 poor metabolizers. - Coadministration of valdecoxib with phenytoin (a CYP 2C9/2C19 substrate) did not affect the pharmacokinetics of phenytoin. - Coadministration of valdecoxib, or its injectable prodrug, with substrates of CYP 2C9 (propofol) and CYP 3A4 (midazolam, alfentanil, fentanyl) did not inhibit the metabolism of these substrates. ## Nonclinical Toxicology - Valdecoxib was not carcinogenic in rats given oral doses up to 7.5 mg/kg/day for males and 1.5 mg/kg/day for females (equivalent to approximately 2- to 6-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) or in mice given oral doses up to 25 mg/kg/day for males and 50 mg/kg/day for females (equivalent to approximately 0.6- to 2.4-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) for two years. - Valdecoxib was not mutagenic in an Ames test or a mutation assay in Chinese hamster ovary (CHO) cells, nor was it clastogenic in a chromosome aberration assay in CHO cells or in an in vivo micronucleus test in rat bone marrow. - Valdecoxib did not impair male rat fertility at oral doses up to 9.0 mg/kg/day (equivalent to approximately 3- to 6-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)). In female rats, a decrease in ovulation with increased pre- and post-implantation loss resulted in decreased live embryos/fetuses at doses ≥2 mg/kg/day (equivalent to approximately 2-fold human exposure at 20 mg QD as measured by the AUC(0–24hr) for valdecoxib). The effects on female fertility were reversible. This effect is expected with inhibition of prostaglandin synthesis and is not the result of irreversible alteration of female reproductive function. # Clinical Studies - The efficacy and clinical utility of BEXTRA Tablets have been demonstrated in osteoarthritis (OA), rheumatoid arthritis (RA) and in the treatment of primary dysmenorrhea. - BEXTRA was evaluated for treatment of the signs and symptoms of osteoarthritis of the knee or hip, in five double-blind, randomized, controlled trials in which 3918 patients were treated for 3 to 6 months. BEXTRA was shown to be superior to placebo in improvement in three domains of OA symptoms: (1) the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness and functional measures in OA, (2) the overall patient assessment of pain, and (3) the overall patient global assessment. The two 3-month pivotal trials in OA generally showed changes statistically significantly different from placebo, and comparable to the naproxen control, in measures of these domains for the 10 mg/day dose. No additional benefit was seen with a valdecoxib 20-mg daily dose. - BEXTRA demonstrated significant reduction compared to placebo in the signs and symptoms of RA, as measured by the ACR (American College of Rheumatology) 20 improvement, a composite defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five: patient global, physician global, patient pain, patient function assessment, and C-reactive protein (CRP). BEXTRA was evaluated for treatment of the signs and symptoms of rheumatoid arthritis in four double-blind, randomized, controlled studies in which 3444 patients were treated for 3 to 6 months. The two 3-month pivotal trials compared valdecoxib to naproxen and placebo. The results for the ACR20 responses in these trials are shown below (Table 2). Trials of BEXTRA in rheumatoid arthritis allowed concomitant use of corticosteroids and/or disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, gold salts, and hydroxychloroquine. No additional benefit was seen with a valdecoxib 20-mg daily dose. - BEXTRA was compared to naproxen sodium 550 mg in two placebo-controlled studies of women with moderate to severe primary dysmenorrhea. The onset of analgesia was within 60 minutes for BEXTRA 20 mg. The onset, magnitude, and duration of analgesic effect with BEXTRA 20 mg were comparable to naproxen sodium 550 mg. - Studies in post-surgical patients (Investigational use) - Three placebo-controlled studies (two coronary artery bypass graft (CABG) surgery studies largely in patients with medial sternotomy placed on cardiopulmonary bypass and a single general surgery study) were conducted to evaluate the safety of the investigational agent, parecoxib sodium (the parenteral pro-drug of valdecoxib) and valdecoxib. Patients received parecoxib sodium for at least 3 days and then were transitioned to valdecoxib for a total treatment duration of 10–14 days. All patients received standard of care analgesia during treatment and all patients received low-dose aspirin prior to randomization and throughout the two CABG surgery studies. - In addition to routine adverse event reporting, pre-specified adverse events of interest were adjudicated according to pre-specified definitions by an independent committee who were blinded to treatment assignment. In the three studies, the overall routine adverse event profiles were similar between active treatments and placebo. - The first CABG surgery study evaluated patients treated with IV parecoxib sodium 40 mg bid for a minimum of 3 days, followed by treatment with valdecoxib 40 mg bid (parecoxib sodium/valdecoxib group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine pre-specified adverse event categories were evaluated (cardiovascular thromboembolic events, pericarditis, new onset or exacerbation of congestive heart failure, renal failure/dysfunction, upper GI ulcer complications, major non-GI bleeds, infections, non-infectious pulmonary complications, and death). There was a significantly (p<0.05) greater incidence of cardiovascular/thromboembolic events (myocardial infarction, ischemia, cerebrovascular accident, deep vein thrombosis and pulmonary embolism) detected in the parecoxib/valdecoxib treatment group compared to the placebo/placebo treatment group for the IV dosing period (2.2% and 0.0% respectively) and over the entire study period (4.8% and 1.3% respectively). Surgical wound complications (most involving the sternal wound) were observed at an increased rate with parecoxib/valdecoxib treatment. - In the second larger CABG surgery study, four pre-specified event categories were evaluated (cardiovascular/thromboembolic; renal dysfunction/renal failure; upper GI ulcer/bleeding; surgical wound complication). Patients were randomized within 24-hours post-CABG surgery to: parecoxib initial dose of 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO (20 mg Q12H) (n=544) for the remainder of a 10 day treatment period; placebo IV followed by valdecoxib PO (n=544); or placebo IV followed by placebo PO (n=548). A significantly (p=0.033) greater incidence of events in the cardiovascular/thromboembolic category was detected in the parecoxib /valdecoxib treatment group (2.0%) compared to the placebo/placebo treatment group (0.5%). Placebo/valdecoxib treatment was also associated with a higher incidence of CV thromboembolic events versus placebo treatment, but this difference did not reach statistical significance. Three of the cardiovascular thromboembolic events in the placebo/valdecoxib treatment group occurred during the placebo treatment period; these patients did not receive valdecoxib. Pre-specified events that occurred with the highest incidence in all three treatment groups involved the category of surgical wound complications, including deep surgical infections and sternal wound healing events (see table below). - General Surgery: In the third study, a large (N=1050) major orthopedic/general surgery trial, patients received an initial dose of parecoxib 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO (20 mg Q12H) (n=525) for the remainder of a 10 day treatment period, or placebo IV followed by placebo PO (n=525). There were no significant differences in the overall safety profile, including the four pre-specified event categories described above for the second CABG surgery study, for parecoxib sodium/valdecoxib compared to placebo treatment in these post-surgical patients (see table below). - No significant differences were observed between the treatment groups - BEXTRA is contraindicated for the treatment of post-operative pain immediately following coronary artery bypass graft surgery and should not be used in this setting . - Cardiovascular Safety Analysis from Osteoarthritis and Rheumatoid Arthritis Studies - Randomized controlled clinical trials with BEXTRA longer than one year have not been conducted, nor have studies powered to detect differences in cardiovascular events in a chronic setting been conducted. - In an analysis of 10 randomized controlled clinical studies in osteoarthritis and rheumatoid arthritis, 4531 patients received BEXTRA in doses ranging from 10 mg to 80 mg for periods of 6 to 52 weeks. The majority of these patients received BEXTRA for 12 weeks or less. This analysis compared the incidence of serious cardiovascular events in BEXTRA-treated patients with the incidence of these events in patients receiving placebo (N=1142) or NSAID therapy (N=2261). In this analysis, no apparent differences were detected in the exposure-adjusted serious cardiovascular thromboembolic event rates between patients receiving BEXTRA, placebo and NSAIDs. - BEXTRA has not been studied in clinical trials beyond 12 months duration. - Gastrointestinal (GI) Endoscopy Studies with Therapeutic Doses - Scheduled upper GI endoscopic evaluations were performed with BEXTRA at doses of 10 and 20 mg daily in over 800 OA patients who were enrolled into two randomized 3-month studies using active comparators and placebo controls (Study 3 and Study 4). These studies enrolled patients free of endoscopic ulcers at baseline and compared rates of endoscopic ulcers, defined as any gastroduodenal ulcer seen endoscopically provided it was of "unequivocal depth" and at least 3 mm in diameter. - In both studies, BEXTRA 10 mg daily was associated with a statistically significant lower incidence of endoscopic gastroduodenal ulcers over the study period compared to the active comparators. Figure 1 summarizes the incidence of gastroduodenal ulcers in Studies 3 and 4 for the placebo, valdecoxib, and active control arms. - Safety Study with Supratherapeutic Doses - Scheduled upper GI endoscopic evaluations were performed in a randomized 6-month study of 1217 patients with OA and RA comparing valdecoxib 20 mg BID (40 mg daily) and 40 mg BID (80 mg daily) (4 to 8 times the recommended therapeutic dose) to naproxen 500 mg BID (Study 5). This study also formally assessed renal events as a primary outcome with supratherapeutic doses of BEXTRA. The renal endpoint was defined as any of the following: new/increase in edema, new/increase in congestive heart failure, increase in blood pressure (BP; >20 mm Hg systolic, >10 mm Hg diastolic), new/increase in BP treatment, new/increase in diuretic therapy, creatinine increase over 30% (or >1.2 mg/dL if baseline 50 mg/dL, 24-hr urinary protein increase to >500 mg (if baseline 0–150 mg or >750 if baseline 151–300 or >1000 if baseline 301–500), serum potassium increase to >6 mEq/L, or serum sodium decrease to <130 mEq/L. - Figure 2 summarizes the incidence rates of gastroduodenal ulcers and renal events that were seen in Study 5. BEXTRA 40 mg daily and 80 mg daily were associated with a statistically significant lower incidence of endoscopic gastroduodenal ulcers over the study period compared to naproxen. The incidence of renal events was significantly different between the BEXTRA 80 mg daily group and naproxen. The clinical relevance of renal events observed with supratherapeutic doses (4 to 8 times the recommended therapeutic dose) of BEXTRA is not known - Renal Safety at the Therapeutic Chronic Dose - The renal effects of valdecoxib compared with placebo and conventional NSAIDs were also assessed by prospectively designed pooled analyses of renal events data (see definition above —SUPRATHERAPEUTIC DOSES) from five placebo- and active-controlled 12-week arthritis trials that included 995 OA or RA patients given valdecoxib 10 mg daily. The incidence of renal events observed in this analysis with valdecoxib 10 mg daily (3%), ibuprofen 800 mg TID (7%), naproxen 500 mg BID (2%) and diclofenac 75 mg BID (4%) were significantly higher than placebo-treated patients (1%). In all treatment groups, the majority of renal events were either due to the occurrence of edema or worsening BP. - Gastrointestinal Ulcers in High-Risk Patients - Subset analyses were performed of patients with risk factors (age, concomitant low-dose aspirin use, history of prior ulcer disease) enrolled in four upper GI endoscopic studies. Table 3 summarizes the trends seen. - The correlation between findings of endoscopic studies, and the incidence of clinically significant serious upper GI events has not been established. - Platelets - In four clinical studies with young and elderly (≥65 years) subjects, single and multiple doses up to 7 days of BEXTRA 10 to 40 mg BID had no effect on platelet aggregation. # How Supplied - BEXTRA Tablets 10 mg are white, film-coated, and capsule-shaped, debossed "10" on one side with a four pointed star shape on the other, supplied as: - BEXTRA Tablets 20 mg are white, film-coated, and capsule-shaped, debossed "20" on one side with a four pointed star shape on the other, supplied as: ## Storage Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) # Images ## Drug Images ## Package and Label Display Panel ### Ingredients and Appearance # Patient Counseling Information - BEXTRA can cause GI discomfort and, rarely, more serious GI side effects, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS — GASTROINTESTINAL (GI) EFFECTS — RISK OF GI ULCERATION, BLEEDING, AND PERFORATION). - Patients should report to their physicians, signs or symptoms of gastrointestinal ulceration or bleeding, weight gain, or edema. - Patients should be instructed to discontinue treatment and seek medical attention at the first signs of a skin reaction (pruritus, rash, erythema, or mucosal lesions) . - Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction. - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and flu-like symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical attention. - In late pregnancy, BEXTRA should be avoided because it may cause premature closure of the ductus arteriosus. # Precautions with Alcohol - Alcohol-Valdecoxib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Bextra® # Look-Alike Drug Names There is limited information regarding Valdecoxib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Valdecoxib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Valdecoxib is a Cyclooxygenase-2 Inhibitor that is FDA approved for the treatment of osteoarthritis, adult rheumatoid arthritis and primary dysmenorrhea. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Abdominal pain, Diarrhea, Flatulence, Indigestion, Nausea, Dizziness, Headache, Rash, Hypertension, Peripheral edema , Backache, Myalgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - For relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis. - For the treatment of primary dysmenorrhea ### Dosage - The recommended dose of BEXTRA Tablets for the relief of the signs and symptoms of arthritis is 10 mg once daily. - The recommended dose of BEXTRA Tablets for treatment of primary dysmenorrhea is 20 mg twice daily, as needed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Valdecoxib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Valdecoxib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Valdecoxib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Valdecoxib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Valdecoxib in pediatric patients. # Contraindications - BEXTRA should not be given to patients who have demonstrated allergic-type reactions to sulfonamides. - BEXTRA Tablets are contraindicated in patients with known hypersensitivity to valdecoxib. BEXTRA should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs are possible in such patients. - BEXTRA is contraindicated for the treatment of post-operative pain immediately following coronary artery bypass graft (CABG) surgery and should not be used in this setting. # Warnings - Serious gastrointestinal toxicity such as bleeding, ulceration and perforation of the stomach, small intestine or large intestine can occur at any time with or without warning symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor gastrointestinal problems such as dyspepsia are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding even in the absence of previous GI tract symptoms. Patients should be informed about the signs and symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation caused by NSAIDs appear to occur in approximately 1% of patients treated for 3 to 6 months and 2–4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. - NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. - Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status. - Valdecoxib contains a sulfonamide moiety and patients with a known history of a sulfonamide allergy may be at a greater risk of skin reactions. Patients without a history of sulfonamide allergy may also be at risk for serious skin reactions. - Serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported through postmarketing surveillance in patients receiving BEXTRA . Fatalities due to Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Patients appear to be at higher risk for these events early in the course of therapy, with the onset of the event occurring in the majority of cases within the first two weeks of treatment. BEXTRA should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Serious skin reactions have been reported with other COX-2 inhibitors during postmarketing experience. The reported rate of these events appears to be greater for BEXTRA as compared to other COX-2 agents. - In postmarketing experience, cases of hypersensitivity reactions (anaphylactic reactions and angioedema) have been reported in patients receiving BEXTRA. These cases have occurred in patients with and without a history of allergic-type reactions to sulfonamides. BEXTRA should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. - Emergency help should be sought in cases where an anaphylactoid reaction occurs. - Patients treated with BEXTRA for pain following coronary artery bypass graft surgery have a higher risk for cardiovascular/thromboembolic events, deep surgical infections or sternal wound complications. BEXTRA is therefore contraindicated for the treatment of postoperative pain following CABG surgery. - No information is available regarding the safe use of BEXTRA Tablets in patients with advanced kidney disease. Therefore, treatment with BEXTRA is not recommended in these patients. If therapy with BEXTRA must be initiated, close monitoring of the patient's kidney function is advisable. - In late pregnancy, BEXTRA should be avoided because it may cause premature closure of the ductus arteriosus. ### Precautions - BEXTRA Tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. - The pharmacological activity of valdecoxib in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. - Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may remain transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs. In controlled clinical trials of valdecoxib, the incidence of borderline (defined as 1.2- to 3.0-fold) elevations of liver tests was 8.0% for valdecoxib and 8.4% for placebo, while approximately 0.3% of patients taking valdecoxib, and 0.2% of patients taking placebo, had notable (defined as greater than 3-fold) elevations of ALT or AST. - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with BEXTRA. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), BEXTRA should be discontinued. - Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and Angiotensin Converting Enzyme (ACE) inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. - Caution should be used when initiating treatment with BEXTRA in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with BEXTRA. Caution is also recommended in patients with preexisting kidney disease. - Anemia is sometimes seen in patients receiving BEXTRA. Patients on long-term treatment with BEXTRA should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. - BEXTRA does not generally affect platelet counts, prothrombin time (PT), or activated partial thromboplastin time (APTT), and does not appear to inhibit platelet aggregation at indicated dosages. - Fluid retention and edema have been observed in some patients taking BEXTRA. Therefore, BEXTRA should be used with caution in patients with fluid retention, hypertension, or heart failure. - Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, BEXTRA should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. - Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. # Adverse Reactions ## Clinical Trials Experience - Of the patients treated with BEXTRA Tablets in controlled arthritis trials, 2665 were patients with OA, and 2684 were patients with RA. More than 4000 patients have received a chronic total daily dose of BEXTRA 10 mg or more. More than 2800 patients have received BEXTRA 10 mg/day, or more, for at least 6 months and 988 of these have received BEXTRA for at least 1 year. - Table 4 lists all adverse events, regardless of causality, that occurred in ≥2.0% of patients receiving BEXTRA 10 and 20 mg/day in studies of three months or longer from 7 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group. - In these placebo- and active-controlled clinical trials, the discontinuation rate due to adverse events was 7.5% for arthritis patients receiving valdecoxib 10 mg daily, 7.9% for arthritis patients receiving valdecoxib 20 mg daily and 6.0%for patients receiving placebo. - In the seven controlled OA and RA studies, the following adverse events occurred in 0.1–1.9% of patients treated with BEXTRA 10–20 mg daily, regardless of causality. - Cellulitis, dermatitis contact - Aggravated hypertension, aneurysm, angina pectoris, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disorder, heart murmur, hypotension - Cerebrovascular disorder, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, tremor, twitching, vertigo - Goiter - Amenorrhea, dysmenorrhea, leukorrhea, mastitis, menstrual disorder, menorrhagia, menstrual bloating, vaginal hemorrhage - Abnormal stools, constipation, diverticulosis, dry mouth, duodenal ulcer, duodenitis, eructation, esophagitis, fecal incontinence, gastric ulcer, gastritis, gastroenteritis, gastroesophageal reflux, hematemesis, hematochezia, hemorrhoids, hemorrhoids bleeding, hiatal hernia, melena, stomatitis, stool frequency increased, tenesmus, tooth disorder, vomiting - Allergy aggravated, allergic reaction, asthenia, chest pain, chills, cyst NOS, generalized edema, face edema, fatigue, fever, hot flushes, halitosis, malaise, pain, periorbital swelling, peripheral pain - Ear abnormality, earache, tinnitus - Bradycardia, palpitation, tachycardia - Anemia - abnormal Hepatic function , hepatitis, ALT increased, AST increased - Impotence, prostatic disorder - Alkaline phosphatase increased, BUN increased, CPK increased, creatinine increased, diabetes mellitus, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia, hypocalcemia, hypokalemia, LDH increased, thirst increased, weight loss, weight gain, xerophthalmia - Arthralgia, fracture accidental, neck stiffness, osteoporosis, synovitis, tendonitis - Breast neoplasm, lipoma, malignant ovarian cyst - Ecchymosis, epistaxis, hematoma NOS, thrombocytopenia - Anorexia, anxiety, appetite increased, confusion, depression, depression aggravated, insomnia, nervousness, morbid dreaming, somnolence - Herpes simplex, herpes zoster, fungal infection, soft tissue infection, viral infection, moniliasis, moniliasis genital, otitis media - Abnormal breath sounds, bronchitis, bronchospasm, coughing, dyspnea, emphysema, laryngitis, pneumonia, pharyngitis, pleurisy, rhinitis - Acne, alopecia, dermatitis, fungal dermatitis , eczema, photosensitivity allergic reaction, pruritus, erythematous rash, maculopapular rash, psoriaform rash, skin dry, skin hypertrophy, skin ulceration, increased sweating, urticaria - Taste perversion - Albuminuria, cystitis, dysuria, hematuria, micturition frequency increased, pyuria, urinary incontinence, urinary tract infection - intermittent Claudication , acquired hemangioma , varicose vein - Blurred vision, cataract, conjunctival hemorrhage, conjunctivitis, eye pain, keratitis, abnormal vision - Eosinophilia, leukopenia, leukocytosis, lymphadenopathy, lymphangitis, lymphopenia - Other serious adverse events that were reported rarely (estimated <0.1%) in clinical trials, regardless of causality, in patients taking BEXTRA: - Hypertensive encephalopathy, vasospasm - Abnormal ECG, aortic stenosis, atrial fibrillation, carotid stenosis, coronary thrombosis, heart block, heart valve disorders, mitral insufficiency, myocardial infarction, myocardial ischemia, pericarditis, syncope, thrombophlebitis, unstable angina, ventricular fibrillation - Convulsions - Hyperparathyroidism - Cervical dysplasia - Appendicitis, colitis with bleeding, dysphagia, esophageal perforation, gastrointestinal bleeding, ileus, intestinal obstruction, peritonitis - Lymphoma-like disorder, pancytopenia - Cholelithiasis - Dehydration - Pathological fracture, osteomyelitis - Benign brain neoplasm, bladder carcinoma, carcinoma, gastric carcinoma, prostate carcinoma, pulmonary carcinoma - Embolism, pulmonary embolism, thrombosis - Manic reaction, psychosis - Acute renal failure - Sepsis - Apnea, pleural effusion, pulmonary edema, pulmonary fibrosis, pulmonary infarction, pulmonary hemorrhage, respiratory insufficiency - Basal cell carcinoma, malignant melanoma - Pyelonephritis, renal calculus - Retinal detachment ## Postmarketing Experience - The following reactions have been identified during postmarketing use of BEXTRA. These reactions have been chosen for inclusion either due to their seriousness, reporting frequency, possible causal relationship to BEXTRA, or a combination of these factors. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - General: Hypersensitivity reactions (including anaphylactic reactions and angioedema) - Gastrointestinal: Pancreatitis - Skin and appendages: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis # Drug Interactions - The drug interaction studies with valdecoxib were performed both with valdecoxib and a rapidly hydrolyzed intravenous prodrug form. The results from trials using the intravenous prodrug are reported in this section as they relate to the role of valdecoxib in drug interactions. - In humans, valdecoxib metabolism is predominantly mediated via CYP 3A4 and 2C9 with glucuronidation being a further (20%) route of metabolism. In vitro studies indicate that valdecoxib is a moderate inhibitor of CYP 2C19 (IC50 = 6 µg/mL or 19 µM) and 2C9 (IC50 = 13 µg/mL or 41 µM), and a weak inhibitor of CYP 2D6 (IC50 = 31 µg/mL or 100 µM) and 3A4 (IC50 = 44 µg/mL or 141 µM). - Concomitant administration of aspirin with valdecoxib may result in an increased risk of GI ulceration and complications compared to valdecoxib alone. Because of its lack of anti-platelet effect valdecoxib is not a substitute for aspirin for cardiovascular prophylaxis. - In a parallel group drug interaction study comparing the intravenous prodrug form of valdecoxib at 40 mg BID (n=10) vs placebo (n=9), valdecoxib had no effect on in vitro aspirin-mediated inhibition of arachidonate- or collagen-stimulated platelet aggregation. - Valdecoxib 10 mg BID did not show a significant effect on the plasma exposure or renal clearance of methotrexate. - Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking BEXTRA concomitantly with ACE-inhibitors. - Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. - Steady state plasma exposure (AUC) of valdecoxib (40 mg BID for 12 days) was decreased by 27% when coadministered with multiple doses (300 mg QD for 12 days) of phenytoin (a CYP 3A4 inducer). Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration. Valdecoxib did not have a statistically significant effect on the pharmacokinetics of phenytoin (a CYP 2C9 and CYP 2C19 substrate). - Drug interaction studies with other anticonvulsants have not been conducted. Routine monitoring should be performed when therapy with BEXTRA is either initiated or discontinued in patients on anticonvulsant therapy. - Dextromethorphan is primarily metabolized by CYP 2D6 and to a lesser extent by 3A4. Coadministration with valdecoxib (40 mg BID for 7 days) resulted in a significant increase in dextromethorphan plasma levels suggesting that, at these doses, valdecoxib is a weak inhibitor of 2D6. Even so, dextromethorphan plasma concentrations in the presence of high doses of valdecoxib were almost 5-fold lower than those seen in CYP 2D6 poor metabolizers suggesting that dose adjustment is not necessary. - Valdecoxib 40 mg BID for 7 days produced significant decreases in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone. Lithium serum concentrations should be monitored closely when initiating or changing therapy with BEXTRA in patients receiving lithium. Lithium carbonate (450 mg BID for 7 days) had no effect on valdecoxib pharmacokinetics. - The effect of valdecoxib on the anticoagulant effect of warfarin (1–8 mg/day) was studied in healthy subjects by coadministration of BEXTRA 40 mg BID for 7 days. Valdecoxib caused a statistically significant increase in plasma exposures of R-warfarin and S-warfarin (12% and 15%, respectively), and in the pharmacodynamic effects (prothrombin time, measured as INR) of warfarin. While mean INR values were only slightly increased with coadministration of valdecoxib, the day-to-day variability in individual INR values was increased. Anticoagulant therapy should be monitored, particularly during the first few weeks, after initiating therapy with BEXTRA in patients receiving warfarin or similar agents. - Ketoconazole and fluconazole are predominantly CYP 3A4 and 2C9 inhibitors, respectively. Concomitant single dose administration of valdecoxib 20 mg with multiple doses of ketoconazole and fluconazole produced a significant increase in exposure of valdecoxib. Plasma exposure (AUC) to valdecoxib was increased 62% when coadministered with fluconazole and 38% when coadministered with ketoconazole. - Glyburide is a CYP 2C9 substrate. Coadministration of valdecoxib (10 mg BID for 7 days) with glyburide (5 mg QD or 10 mg BID) did not affect the pharmacokinetics (exposure) of glyburide. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2–7)) with glyburide (5 mg QD) did not affect either the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of glyburide. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2–7)) with glyburide (10 mg glyburide BID) resulted in 21% increase in glyburide AUC(0–12hr) and a 16% increase in glyburide Cmax leading to a 16%decrease in glucose AUC(0–24hr). Insulin parameters were not affected. Because changes in glucose concentrations with valdecoxib coadministration were within the normal variability and individual glucose concentrations were above or near 70 mg/dL, dose adjustment for glyburide (5 mg QD and 10 mg BID) with valdecoxib coadministration (up to 40 mg QD) is not indicated. Coadministration of glyburide with doses higher than 40 mg valdecoxib (e.g., 40 mg BID) has not been studied. - Omeprazole is a CYP 3A4 substrate and CYP 2C19 substrate and inhibitor. Valdecoxib steady state plasma concentrations (40 mg BID) were not affected significantly with multiple doses of omeprazole (40 mg QD). Coadministration with valdecoxib increased exposure of omeprazole (AUC) by 46%. Drugs whose absorption is sensitive to pH may be negatively impacted by concomitant administration of omeprazole and valdecoxib. However, because higher doses (up to 360 mg QD) of omeprazole are tolerated in Zollinger-Ellison (ZE) patients, no dose adjustment for omeprazole is recommended at current doses. Coadministration of valdecoxib with doses higher than 40 mg QD omeprazole has not been studied. - Valdecoxib (40 mg BID) did not induce the metabolism of the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg combination, Ortho-Novum 1/35®). Coadministration of valdecoxib and Ortho-Novum 1/35® increased the exposure of norethindrone and ethinyl estradiol by 20% and 34%, respectively. Although there is little risk for loss of contraceptive efficacy, the clinical significance of these increased exposures in terms of safety is not known. These increased exposures of norethindrone and ethinyl estradiol should be taken into consideration when selecting an oral contraceptive for women taking valdecoxib. - Diazepam (Valium®) is a CYP 3A4 and CYP 2C19 substrate. Plasma exposure of diazepam (10 mg BID) was increased by 28% following administration of valdecoxib (40 mg BID) for 12 days, while plasma exposure of valdecoxib (40 mg BID) was not substantially increased following administration of diazepam (10 mg BID) for 12 days. Although the magnitude of changes in diazepam plasma exposure when coadministered with valdecoxib were not sufficient to warrant dosage adjustments, patients may experience enhanced sedative side effects caused by increased exposure of diazepam under this circumstance. Patients should be cautioned against engaging in hazardous activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - The incidence of fetuses with skeletal anomalies such as semi-bipartite thoracic vertebra centra and fused sternebrae was slightly higher in rabbits at an oral dose of 40 mg/kg/day (equivalent to approximately 72-fold human exposures at 20 mg QD as measured by the AUC(0–24hr)) throughout organogenesis. Valdecoxib was not teratogenic in rabbits up to an oral dose of 10 mg/kg/day (equivalent to approximately 8-fold human exposures at 20 mg QD as measured by the AUC(0–24hr)). - Valdecoxib was not teratogenic in rats up to an oral dose of 10 mg/kg/day (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)). There are no studies in pregnant women. However, valdecoxib crosses the placenta in rats and rabbits. BEXTRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Valdecoxib caused increased pre- and post-implantation loss with reduced live fetuses at oral doses ≥10 mg/kg/day (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) in rats and an oral dose of 40 mg/kg/day (equivalent to approximately 72-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) in rabbits throughout organogenesis. In addition, reduced neonatal survival and decreased neonatal body weight when rats were treated with valdecoxib at oral doses ≥6 mg/kg/day (equivalent to approximately 7-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) throughout organogenesis and lactation period. No studies have been conducted to evaluate the effect of valdecoxib on the closure of the ductus arteriosus in humans. Therefore, as with other drugs known to inhibit prostaglandin synthesis, use of BEXTRA during the third trimester of pregnancy should be avoided. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valdecoxib in women who are pregnant. ### Labor and Delivery - Valdecoxib produced no evidence of delayed labor or parturition at oral doses up to 10 mg/kg/day in rats (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)). The effects of BEXTRA on labor and delivery in pregnant women are unknown. ### Nursing Mothers - Valdecoxib and its active metabolite are excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse reactions in nursing infants from BEXTRA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and the importance of nursing to the infant. ### Pediatric Use - Safety and effectiveness of BEXTRA in pediatric patients below the age of 18 years have not been evaluated. ### Geriatic Use - Of the patients who received BEXTRA in arthritis clinical trials of three months duration, or greater, approximately 2100 were 65 years of age or older, including 570 patients who were 75 years or older. No overall differences in effectiveness were observed between these patients and younger patients. ### Gender There is no FDA guidance on the use of Valdecoxib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Valdecoxib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Valdecoxib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Valdecoxib in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Valdecoxib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Valdecoxib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - If therapy with BEXTRA must be initiated, close monitoring of the patient's kidney function is advisable - A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with BEXTRA. - Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. - Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration. - Lithium serum concentrations should be monitored closely when initiating or changing therapy with BEXTRA in patients receiving lithium. - Anticoagulant therapy should be monitored, particularly during the first few weeks, after initiating therapy with BEXTRA in patients receiving warfarin or similar agents. # IV Compatibility There is limited information regarding IV Compatibility of Valdecoxib in the drug label. # Overdosage - Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. - Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. - Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Hemodialysis removed only about 2% of administered valdecoxib from the systemic circulation of 8 patients with end-stage renal disease and, based on its degree of plasma protein binding (>98%), dialysis is unlikely to be useful in overdose. Forced diuresis, alkalinization of urine, or hemoperfusion also may not be useful due to high protein binding. # Pharmacology ## Mechanism of Action - Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties in animal models. The mechanism of action is believed to be due to inhibition of prostaglandin synthesis primarily through inhibition of cyclooxygenase-2 (COX-2). At therapeutic plasma concentrations in humans valdecoxib does not inhibit cyclooxygenase-1 (COX-1). ## Structure - Valdecoxib is chemically designated as 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide and is a diaryl substituted isoxazole. It has the following chemical structure: - The empirical formula for valdecoxib is C16H14N2O3S, and the molecular weight is 314.36. Valdecoxib is a white crystalline powder that is relatively insoluble in water (10 µg/mL) at 25°C and pH 7.0, soluble in methanol and ethanol, and freely soluble in organic solvents and alkaline (pH=12) aqueous solutions. - BEXTRA Tablets for oral administration contain either 10 mg or 20 mg of valdecoxib. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol, polysorbate 80, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Valdecoxib in the drug label. ## Pharmacokinetics - Valdecoxib achieves maximal plasma concentrations in approximately 3 hours. The absolute bioavailability of valdecoxib is 83% following oral administration of BEXTRA compared to intravenous infusion of valdecoxib. - Dose proportionality was demonstrated after single doses (1–400 mg) of valdecoxib. With multiple doses (up to 100 mg/day for 14 days), valdecoxib exposure as measured by the AUC, increases in a more than proportional manner at doses above 10 mg BID. Steady state plasma concentrations of valdecoxib are achieved by day 4. - The steady state pharmacokinetic parameters of valdecoxib in healthy male subjects are shown in Table 1. - No clinically significant age or gender differences were seen in pharmacokinetic parameters that would require dosage adjustments. - Effect of Food and Antacid - BEXTRA can be taken with or without food. Food had no significant effect on either the peak plasma concentration (Cmax) or extent of absorption (AUC) of valdecoxib when BEXTRA was taken with a high fat meal. The time to peak plasma concentration (Tmax), however, was delayed by 1–2 hours. Administration of BEXTRA with antacid (aluminum/magnesium hydroxide) had no significant effect on either the rate or extent of absorption of valdecoxib. - Plasma protein binding for valdecoxib is about 98% over the concentration range (21–2384 ng/mL). Steady state apparent volume of distribution (Vss/F) of valdecoxib is approximately 86 L after oral administration. Valdecoxib and its active metabolite preferentially partition into erythrocytes with a blood to plasma concentration ratio of about 2.5:1. This ratio remains approximately constant with time and therapeutic blood concentrations. - In humans, valdecoxib undergoes extensive hepatic metabolism involving both P450 isoenzymes (3A4 and 2C9) and non-P450 dependent pathways (i.e., glucuronidation). Concomitant administration of BEXTRA with known CYP 3A4 and 2C9 inhibitors (e.g., fluconazole and ketoconazole) can result in increased plasma exposure of valdecoxib. - One active metabolite of valdecoxib has been identified in human plasma at approximately 10% the concentration of valdecoxib. This metabolite, which is a less potent COX-2 specific inhibitor than the parent, also undergoes extensive metabolism and constitutes less than 2% of the valdecoxib dose excreted in the urine and feces. Due to its low concentration in the systemic circulation, it is not likely to contribute significantly to the efficacy profile of BEXTRA. - Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. The apparent oral clearance (CL/F) of valdecoxib is about 6 L/hr. The mean elimination half-life (T1/2) ranges from 8–11 hours, and increases with age. - In elderly subjects (> 65 years), weight-adjusted steady state plasma concentrations (AUC(0–12hr)) are about 30% higher than in young subjects. No dose adjustment is needed based on age. - BEXTRA has not been investigated in pediatric patients below 18 years of age. - Pharmacokinetic differences due to race have not been identified in clinical and pharmacokinetic studies conducted to date. - Valdecoxib plasma concentrations are significantly increased (130%) in patients with moderate (Child-Pugh Class B) hepatic impairment. In clinical trials, doses of BEXTRA above those recommended have been associated with fluid retention. Hence, treatment with BEXTRA should be initiated with caution in patients with mild to moderate hepatic impairment and fluid retention. The use of BEXTRA in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. - The pharmacokinetics of valdecoxib have been studied in patients with varying degrees of renal impairment. Because renal elimination of valdecoxib is not important to its disposition, no clinically significant changes in valdecoxib clearance were found even in patients with severe renal impairment or in patients undergoing renal dialysis. In patients undergoing hemodialysis the plasma clearance (CL/F) of valdecoxib was similar to the CL/F found in healthy elderly subjects (CL/F about 6 to 7 L/hr.) with normal renal function (based on creatinine clearance). - NSAIDs have been associated with worsening renal function and use in advanced renal disease is not recommended (see PRECAUTIONS — RENAL EFFECTS). - For quantitative information on the following drug interaction studies, see PRECAUTIONS — DRUG INTERACTIONS. - Valdecoxib undergoes both P450 (CYP) dependent and non-P450 dependent (glucuronidation) metabolism. In vitro studies indicate that valdecoxib is not a significant inhibitor of CYP 1A2, 3A4, or 2D6 and is a weak inhibitor of CYP 2C9 and a weak to moderate inhibitor of CYP 2C19 at therapeutic concentrations. The P450-mediated metabolic pathway of valdecoxib predominantly involves the 3A4 and 2C9 isozymes. Using prototype inhibitors and substrates of these isozymes, the following results were obtained. Coadministration of a known inhibitor of CYP 2C9/3A4 (fluconazole) and a CYP 3A4 inhibitor (ketoconazole) enhanced the total plasma exposure (AUC) of valdecoxib. Coadministration of valdecoxib with a CYP 3A4 inducer (phenytoin) decreased total plasma exposure (AUC) of valdecoxib. - Coadministration of valdecoxib with warfarin (a CYP 2C9 substrate) caused a small, but statistically significant increase in plasma exposures of R-warfarin and S-warfarin, and also in the pharmacodynamic effects (International Normalized Ratio-INR) of warfarin. - Coadministration of valdecoxib with diazepam (a CYP 2C19/3A4 substrate) resulted in increased exposure of diazepam, but not its major metabolite, desmethyldiazepam. - Coadministration of valdecoxib with glyburide (a CYP 2C9 substrate) (40 mg valdecoxib QD with 10 mg glyburide BID) resulted in increased exposure of glyburide. - Coadministration of valdecoxib with an oral contraceptive, 1 mg norethindrone/0.035 mg ethinyl estradiol (CYP 3A4 substrates), resulted in increased exposure of both norethindrone and ethinyl estradiol. - Coadministration of valdecoxib with omeprazole (a CYP 3A4/2C19 substrate) caused an increase in omeprazole exposure. - Coadministration of valdecoxib with dextromethorphan (a CYP 2D6/3A4 substrate) resulted in an increase in dextromethorphan plasma levels above those seen in subjects with normal levels of CYP 2D6. Even so these levels were almost 5-fold lower than those seen in CYP 2D6 poor metabolizers. - Coadministration of valdecoxib with phenytoin (a CYP 2C9/2C19 substrate) did not affect the pharmacokinetics of phenytoin. - Coadministration of valdecoxib, or its injectable prodrug, with substrates of CYP 2C9 (propofol) and CYP 3A4 (midazolam, alfentanil, fentanyl) did not inhibit the metabolism of these substrates. ## Nonclinical Toxicology - Valdecoxib was not carcinogenic in rats given oral doses up to 7.5 mg/kg/day for males and 1.5 mg/kg/day for females (equivalent to approximately 2- to 6-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) or in mice given oral doses up to 25 mg/kg/day for males and 50 mg/kg/day for females (equivalent to approximately 0.6- to 2.4-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)) for two years. - Valdecoxib was not mutagenic in an Ames test or a mutation assay in Chinese hamster ovary (CHO) cells, nor was it clastogenic in a chromosome aberration assay in CHO cells or in an in vivo micronucleus test in rat bone marrow. - Valdecoxib did not impair male rat fertility at oral doses up to 9.0 mg/kg/day (equivalent to approximately 3- to 6-fold human exposure at 20 mg QD as measured by the AUC(0–24hr)). In female rats, a decrease in ovulation with increased pre- and post-implantation loss resulted in decreased live embryos/fetuses at doses ≥2 mg/kg/day (equivalent to approximately 2-fold human exposure at 20 mg QD as measured by the AUC(0–24hr) for valdecoxib). The effects on female fertility were reversible. This effect is expected with inhibition of prostaglandin synthesis and is not the result of irreversible alteration of female reproductive function. # Clinical Studies - The efficacy and clinical utility of BEXTRA Tablets have been demonstrated in osteoarthritis (OA), rheumatoid arthritis (RA) and in the treatment of primary dysmenorrhea. - BEXTRA was evaluated for treatment of the signs and symptoms of osteoarthritis of the knee or hip, in five double-blind, randomized, controlled trials in which 3918 patients were treated for 3 to 6 months. BEXTRA was shown to be superior to placebo in improvement in three domains of OA symptoms: (1) the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness and functional measures in OA, (2) the overall patient assessment of pain, and (3) the overall patient global assessment. The two 3-month pivotal trials in OA generally showed changes statistically significantly different from placebo, and comparable to the naproxen control, in measures of these domains for the 10 mg/day dose. No additional benefit was seen with a valdecoxib 20-mg daily dose. - BEXTRA demonstrated significant reduction compared to placebo in the signs and symptoms of RA, as measured by the ACR (American College of Rheumatology) 20 improvement, a composite defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five: patient global, physician global, patient pain, patient function assessment, and C-reactive protein (CRP). BEXTRA was evaluated for treatment of the signs and symptoms of rheumatoid arthritis in four double-blind, randomized, controlled studies in which 3444 patients were treated for 3 to 6 months. The two 3-month pivotal trials compared valdecoxib to naproxen and placebo. The results for the ACR20 responses in these trials are shown below (Table 2). Trials of BEXTRA in rheumatoid arthritis allowed concomitant use of corticosteroids and/or disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, gold salts, and hydroxychloroquine. No additional benefit was seen with a valdecoxib 20-mg daily dose. - BEXTRA was compared to naproxen sodium 550 mg in two placebo-controlled studies of women with moderate to severe primary dysmenorrhea. The onset of analgesia was within 60 minutes for BEXTRA 20 mg. The onset, magnitude, and duration of analgesic effect with BEXTRA 20 mg were comparable to naproxen sodium 550 mg. - Studies in post-surgical patients (Investigational use) - Three placebo-controlled studies (two coronary artery bypass graft (CABG) surgery studies largely in patients with medial sternotomy placed on cardiopulmonary bypass and a single general surgery study) were conducted to evaluate the safety of the investigational agent, parecoxib sodium (the parenteral pro-drug of valdecoxib) and valdecoxib. Patients received parecoxib sodium for at least 3 days and then were transitioned to valdecoxib for a total treatment duration of 10–14 days. All patients received standard of care analgesia during treatment and all patients received low-dose aspirin prior to randomization and throughout the two CABG surgery studies. - In addition to routine adverse event reporting, pre-specified adverse events of interest were adjudicated according to pre-specified definitions by an independent committee who were blinded to treatment assignment. In the three studies, the overall routine adverse event profiles were similar between active treatments and placebo. - The first CABG surgery study evaluated patients treated with IV parecoxib sodium 40 mg bid for a minimum of 3 days, followed by treatment with valdecoxib 40 mg bid (parecoxib sodium/valdecoxib group) (n=311) or placebo/placebo (n=151) in a 14-day, double-blind placebo-controlled study. Nine pre-specified adverse event categories were evaluated (cardiovascular thromboembolic events, pericarditis, new onset or exacerbation of congestive heart failure, renal failure/dysfunction, upper GI ulcer complications, major non-GI bleeds, infections, non-infectious pulmonary complications, and death). There was a significantly (p<0.05) greater incidence of cardiovascular/thromboembolic events (myocardial infarction, ischemia, cerebrovascular accident, deep vein thrombosis and pulmonary embolism) detected in the parecoxib/valdecoxib treatment group compared to the placebo/placebo treatment group for the IV dosing period (2.2% and 0.0% respectively) and over the entire study period (4.8% and 1.3% respectively). Surgical wound complications (most involving the sternal wound) were observed at an increased rate with parecoxib/valdecoxib treatment. - In the second larger CABG surgery study, four pre-specified event categories were evaluated (cardiovascular/thromboembolic; renal dysfunction/renal failure; upper GI ulcer/bleeding; surgical wound complication). Patients were randomized within 24-hours post-CABG surgery to: parecoxib initial dose of 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO (20 mg Q12H) (n=544) for the remainder of a 10 day treatment period; placebo IV followed by valdecoxib PO (n=544); or placebo IV followed by placebo PO (n=548). A significantly (p=0.033) greater incidence of events in the cardiovascular/thromboembolic category was detected in the parecoxib /valdecoxib treatment group (2.0%) compared to the placebo/placebo treatment group (0.5%). Placebo/valdecoxib treatment was also associated with a higher incidence of CV thromboembolic events versus placebo treatment, but this difference did not reach statistical significance. Three of the cardiovascular thromboembolic events in the placebo/valdecoxib treatment group occurred during the placebo treatment period; these patients did not receive valdecoxib. Pre-specified events that occurred with the highest incidence in all three treatment groups involved the category of surgical wound complications, including deep surgical infections and sternal wound healing events (see table below). - General Surgery: In the third study, a large (N=1050) major orthopedic/general surgery trial, patients received an initial dose of parecoxib 40 mg IV, then 20 mg IV Q12H for a minimum of 3 days followed by valdecoxib PO (20 mg Q12H) (n=525) for the remainder of a 10 day treatment period, or placebo IV followed by placebo PO (n=525). There were no significant differences in the overall safety profile, including the four pre-specified event categories described above for the second CABG surgery study, for parecoxib sodium/valdecoxib compared to placebo treatment in these post-surgical patients (see table below). - No significant differences were observed between the treatment groups - BEXTRA is contraindicated for the treatment of post-operative pain immediately following coronary artery bypass graft surgery and should not be used in this setting . - Cardiovascular Safety Analysis from Osteoarthritis and Rheumatoid Arthritis Studies - Randomized controlled clinical trials with BEXTRA longer than one year have not been conducted, nor have studies powered to detect differences in cardiovascular events in a chronic setting been conducted. - In an analysis of 10 randomized controlled clinical studies in osteoarthritis and rheumatoid arthritis, 4531 patients received BEXTRA in doses ranging from 10 mg to 80 mg for periods of 6 to 52 weeks. The majority of these patients received BEXTRA for 12 weeks or less. This analysis compared the incidence of serious cardiovascular events in BEXTRA-treated patients with the incidence of these events in patients receiving placebo (N=1142) or NSAID therapy (N=2261). In this analysis, no apparent differences were detected in the exposure-adjusted serious cardiovascular thromboembolic event rates between patients receiving BEXTRA, placebo and NSAIDs. - BEXTRA has not been studied in clinical trials beyond 12 months duration. - Gastrointestinal (GI) Endoscopy Studies with Therapeutic Doses - Scheduled upper GI endoscopic evaluations were performed with BEXTRA at doses of 10 and 20 mg daily in over 800 OA patients who were enrolled into two randomized 3-month studies using active comparators and placebo controls (Study 3 and Study 4). These studies enrolled patients free of endoscopic ulcers at baseline and compared rates of endoscopic ulcers, defined as any gastroduodenal ulcer seen endoscopically provided it was of "unequivocal depth" and at least 3 mm in diameter. - In both studies, BEXTRA 10 mg daily was associated with a statistically significant lower incidence of endoscopic gastroduodenal ulcers over the study period compared to the active comparators. Figure 1 summarizes the incidence of gastroduodenal ulcers in Studies 3 and 4 for the placebo, valdecoxib, and active control arms. - Safety Study with Supratherapeutic Doses - Scheduled upper GI endoscopic evaluations were performed in a randomized 6-month study of 1217 patients with OA and RA comparing valdecoxib 20 mg BID (40 mg daily) and 40 mg BID (80 mg daily) (4 to 8 times the recommended therapeutic dose) to naproxen 500 mg BID (Study 5). This study also formally assessed renal events as a primary outcome with supratherapeutic doses of BEXTRA. The renal endpoint was defined as any of the following: new/increase in edema, new/increase in congestive heart failure, increase in blood pressure (BP; >20 mm Hg systolic, >10 mm Hg diastolic), new/increase in BP treatment, new/increase in diuretic therapy, creatinine increase over 30% (or >1.2 mg/dL if baseline <0.9 mg/dL), BUN increase over 200% or >50 mg/dL, 24-hr urinary protein increase to >500 mg (if baseline 0–150 mg or >750 if baseline 151–300 or >1000 if baseline 301–500), serum potassium increase to >6 mEq/L, or serum sodium decrease to <130 mEq/L. - Figure 2 summarizes the incidence rates of gastroduodenal ulcers and renal events that were seen in Study 5. BEXTRA 40 mg daily and 80 mg daily were associated with a statistically significant lower incidence of endoscopic gastroduodenal ulcers over the study period compared to naproxen. The incidence of renal events was significantly different between the BEXTRA 80 mg daily group and naproxen. The clinical relevance of renal events observed with supratherapeutic doses (4 to 8 times the recommended therapeutic dose) of BEXTRA is not known - Renal Safety at the Therapeutic Chronic Dose - The renal effects of valdecoxib compared with placebo and conventional NSAIDs were also assessed by prospectively designed pooled analyses of renal events data (see definition above —SUPRATHERAPEUTIC DOSES) from five placebo- and active-controlled 12-week arthritis trials that included 995 OA or RA patients given valdecoxib 10 mg daily. The incidence of renal events observed in this analysis with valdecoxib 10 mg daily (3%), ibuprofen 800 mg TID (7%), naproxen 500 mg BID (2%) and diclofenac 75 mg BID (4%) were significantly higher than placebo-treated patients (1%). In all treatment groups, the majority of renal events were either due to the occurrence of edema or worsening BP. - Gastrointestinal Ulcers in High-Risk Patients - Subset analyses were performed of patients with risk factors (age, concomitant low-dose aspirin use, history of prior ulcer disease) enrolled in four upper GI endoscopic studies. Table 3 summarizes the trends seen. - The correlation between findings of endoscopic studies, and the incidence of clinically significant serious upper GI events has not been established. - Platelets - In four clinical studies with young and elderly (≥65 years) subjects, single and multiple doses up to 7 days of BEXTRA 10 to 40 mg BID had no effect on platelet aggregation. # How Supplied - BEXTRA Tablets 10 mg are white, film-coated, and capsule-shaped, debossed "10" on one side with a four pointed star shape on the other, supplied as: - BEXTRA Tablets 20 mg are white, film-coated, and capsule-shaped, debossed "20" on one side with a four pointed star shape on the other, supplied as: ## Storage Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) # Images ## Drug Images ## Package and Label Display Panel ### Ingredients and Appearance # Patient Counseling Information - BEXTRA can cause GI discomfort and, rarely, more serious GI side effects, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS — GASTROINTESTINAL (GI) EFFECTS — RISK OF GI ULCERATION, BLEEDING, AND PERFORATION). - Patients should report to their physicians, signs or symptoms of gastrointestinal ulceration or bleeding, weight gain, or edema. - Patients should be instructed to discontinue treatment and seek medical attention at the first signs of a skin reaction (pruritus, rash, erythema, or mucosal lesions) . - Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction. - Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and flu-like symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical attention. - In late pregnancy, BEXTRA should be avoided because it may cause premature closure of the ductus arteriosus. # Precautions with Alcohol - Alcohol-Valdecoxib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Bextra®[1] # Look-Alike Drug Names There is limited information regarding Valdecoxib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Bextra
8d9306112dbd6f8e23338cac75815b06641b9a3e	wikidoc	Bicifadine	Bicifadine Bicifadine is a serotonin-norepinephrine reuptake inhibitor (SNRI) developed by DOV Pharmaceutical. It has been developed as an analgesic and is currently under development for the treatment of various pain conditions. Phase III trials were completed in 2006 for treating chronic low back pain, and the drug is currently being tested to assess its efficacy in treating pain associated with osteoarthritis, acute post-surgical pain, neuropathic pain and pain associated with dental surgery. Bicifadine represents a novel class of drug using a non-opioid, non-NSAID mechanism for the treatment of pain, which should have less abuse potential than opioid drugs. It is not the first SNRI used for pain treatment, as the older drug duloxetine has previously been approved for the treatment of neuropathic pain, and also some atypical opioid drugs such as tramadol and the newer agent tapentadol exhibit some reuptake inhibition properties that contribute to their therapeutic effects. Preliminary results suggest that bicifadine has an analgesic efficacy slightly stronger than codeine and approximately equivalent to tramadol, although side effects such as nausea and headache were more common with bicifadine than with tramadol.	Bicifadine Bicifadine is a serotonin-norepinephrine reuptake inhibitor (SNRI) developed by DOV Pharmaceutical.[1] It has been developed as an analgesic and is currently under development for the treatment of various pain conditions.[2] Phase III trials were completed in 2006 for treating chronic low back pain, and the drug is currently being tested to assess its efficacy in treating pain associated with osteoarthritis, acute post-surgical pain, neuropathic pain and pain associated with dental surgery.[1] Bicifadine represents a novel class of drug using a non-opioid, non-NSAID mechanism for the treatment of pain,[3][4] which should have less abuse potential than opioid drugs. It is not the first SNRI used for pain treatment, as the older drug duloxetine has previously been approved for the treatment of neuropathic pain, and also some atypical opioid drugs such as tramadol and the newer agent tapentadol exhibit some reuptake inhibition properties that contribute to their therapeutic effects. Preliminary results suggest that bicifadine has an analgesic efficacy slightly stronger than codeine and approximately equivalent to tramadol, although side effects such as nausea and headache were more common with bicifadine than with tramadol.[2]	https://www.wikidoc.org/index.php/Bicifadine
42554fdd10c722fde2457ba40ae4ebda789a5010	wikidoc	Bifeprunox	Bifeprunox Bifeprunox is a novel atypical antipsychotic agent which, along with SLV313, aripiprazole and SSR-181507 combines minimal D2 receptor agonism with 5-HT receptor agonism. Bifeprunox has a novel mechanism of action. Conventional antipsychotics are classed into typical and atypical. The typical antipsychotics, such as chlorpromazine and haloperidol are potent D2 receptor antagonists. The atypical antipsychotics started with clozapine, these are classified as multireceptor interacting compounds, acting as an agonist towards 5-HT1A and an antagonist towards D2 receptors among other 5-HT and DA receptors. Bifeprunox and other novel atypical antipsychotics will instead of antagonizing D2 receptors, will act as partial agonists, as well as agonists towards 5-HT1A receptors. An NDA for Bifeprunox was filed by the US FDA in January, 2007. The FDA rejected the application in August, 2007. In the EU, Bifeprunox is still in Phase III clinical trials.	Bifeprunox Bifeprunox is a novel atypical antipsychotic agent which, along with SLV313, aripiprazole and SSR-181507 combines minimal D2 receptor agonism with 5-HT receptor agonism. [1] Bifeprunox has a novel mechanism of action. Conventional antipsychotics are classed into typical and atypical. The typical antipsychotics, such as chlorpromazine and haloperidol are potent D2 receptor antagonists. The atypical antipsychotics started with clozapine, these are classified as multireceptor interacting compounds, acting as an agonist towards 5-HT1A and an antagonist towards D2 receptors among other 5-HT and DA receptors. Bifeprunox and other novel atypical antipsychotics will instead of antagonizing D2 receptors, will act as partial agonists, as well as agonists towards 5-HT1A receptors. [2] An NDA for Bifeprunox was filed by the US FDA in January, 2007. The FDA rejected the application in August, 2007.[3] In the EU, Bifeprunox is still in Phase III clinical trials.	https://www.wikidoc.org/index.php/Bifeprunox
0c10993fc9598586904406b418bc3c4f271cacd1	wikidoc	Bifluoride	Bifluoride The bifluoride, or hydrogen(difluoride), ion is the species HF2−. This centrosymmetric triatomic anion features the strongest known hydrogen bond, with an F−H length of 114 pm and a bond strength of >155 kJ mol−1. A molecular orbital diagram reveals the atoms to be held together by a 3-center 4-electron bond. Hydrogen(difluoride) is written as one word because it is an anion. Hydrogen difluoride would imply an electrically neutral compound, HF2, which does not exist. # Salts Some HF2− salts are common, examples include potassium hydrogen fluoride, KHF2, and . In fact many salts claimed to be anhydrous sources of fluoride (e.g. tetra-n-butylammonium fluoride) contain this anion. # Autodissociation of pure HF The bifluoride ion also contributes to the unusually high auto-protolysis constant of liquid anhydrous hydrofluoric acid, which autodissociates in a manner similar to the self-ionization of water. This equilibrium can be denoted as However, both the H+ and F− ions are solvated by HF, so a better descriptive equation is	Bifluoride The bifluoride, or hydrogen(difluoride), ion is the species HF2−. This centrosymmetric triatomic anion features the strongest known hydrogen bond, with an F−H length of 114 pm[1] and a bond strength of >155 kJ mol−1.[2] A molecular orbital diagram reveals the atoms to be held together by a 3-center 4-electron bond.[3] Hydrogen(difluoride) is written as one word because it is an anion. Hydrogen difluoride would imply an electrically neutral compound, HF2, which does not exist. # Salts Some HF2− salts are common, examples include potassium hydrogen fluoride, KHF2, and [NH4][HF2]. In fact many salts claimed to be anhydrous sources of fluoride (e.g. tetra-n-butylammonium fluoride) contain this anion. # Autodissociation of pure HF The bifluoride ion also contributes to the unusually high auto-protolysis constant of liquid anhydrous hydrofluoric acid, which autodissociates in a manner similar to the self-ionization of water. This equilibrium can be denoted as However, both the H+ and F− ions are solvated by HF, so a better descriptive equation is	https://www.wikidoc.org/index.php/Bifluoride

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