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c05b263e1143e168a54c8a47ffaae40189959547	wikidoc	Berylliosis	Berylliosis Synonyms and keywords: Chronic beryllium disorder; CBD # Overview Berylliosis or chronic beryllium disorder (CBD) is a chronic allergic-type lung response and chronic lung disease caused by exposure to beryllium and its compounds. The condition is incurable but symptoms can be treated. Berylliosis was first discovered by Dr. Harriet Hardy, an American pathologist, in 1945 following an outbreak of respiratory illnesses affecting nearby factory workers. Berylliosis may be classified as a rare disorder and an occupational disease. Exposure to beryllium can cause cell-mediated immunity. In each subsequent exposure macrophages and CD4+ helper T - lymphocytes accumulation in the lungs. As a result macrophages, CD4+ helper T - lymphocytes and plasma cells accumulate to form noncaseating granulomas that cause fibrosis. Granulomas are seen in other chronic diseases, such as tuberculosis, sarcoidosis, and it can occasionally be hard to distinguish berylliosis from these disorders. # Historical Perspective - Berylliosis was first discovered by Dr. Harriet Hardy, an American pathologist, in 1945 following an outbreak of respiratory illnesses affecting nearby factory workers. - In 1946, Hardy established the National Beryllium Registry at the Massachusetts General Hospital. # Classification - There is no formal classification system established for berylliosis. - Berylliosis may be classified as a rare disorder and an occupational disease. # Pathophysiology - Exposure to beryllium can cause cell-mediated immunity, which can sensitize the T cells to beryllium. - In each subsequent exposure macrophage and CD4+ helper T - lymphocytes accumulation in the lungs. - As a result macrophages, CD4+ T lymphocyte and plasma cell accumulate to form noncaseating granulomas that cause fibrosis. - Beryllium is presented to CD4+ T cell by antigen-presenting cells, principally in HLA-DP molecules. T cells in the blood lungs or other organs, in turn, recognize the beryllium, proliferate and form T cell clones. These cause the release of proinflammatory cytokines. such as tumor necrosis factor-alpha, IL-2 and interferon-gamma. These cytokines amplify the immune response, as result formation of mononuclear cell infiltrates and noncaseating granulomas in target organs where beryllium has deposited. - On average about 2 to 6 % of beryllium exposed people develop beryllium sensitized ( defined by positive blood lymphocyte proliferation salt in vitro ) with most progressing to disease. In certain high-risk groups such as beryllium metal and alloy machinists, chronic beryllium disease prevalence is > 17 % workers with bystander exposures, such as secretaries and security guards, also develop sensitization and disease but at lower rates. The typical pathologic consequence is a diffuse pulmonary, hilar, and mediastinal lymph node granulomatous reaction that is histologically indistinguishable from sarcoidosis. - Early granuloma formation with mononuclear and giant cells can also occur. - Many lymphocytes are found when the cell is washed from the lungs ( bronchoalveolar lavage BAL during bronchoscopy. - These T cells proliferate when exposed to beryllium in vitro, much as the blood cells do ( a test called beryllium lymphocyte proliferation test BeLPT ). # Causes - Chronic exposure to beryllium - Genetic predisposition ( Mutation at the HL-A DPB1 Glu69 position increase the prevalence of beryllium sensitization. # Differentiating Berylliosis from other Diseases Granulomas are seen in other chronic diseases, such as tuberculosis, sarcoidosis, and it can occasionally be hard to distinguish berylliosis from these disorders. # Risk Factors - Extended exposure with beryllium - Genetic predisposition ( Mutation at the HL-A DPB1 Glu69 position increase the prevalence of beryllium sensitization. # Natural History, Complications, and Prognosis ## Natural History - Patients with chronic beryllium disease often have dyspnea, cough, weight loss, and a variable chest X-ray pattern, typically showing nodular opacities in the mid and upper lung zones, frequently with hilar and mediastinal adenopathy. - Patients complain of insidious and progressive exertional dyspnea, cough, chest pain, weight loss, night sweats, and fatigue. Symptoms may develop within months of first exposure or more than 30 years after exposure and some people remain asymptomatic. - Acute beryllium disease is distinguished from chronic disease based on the history of the very high level of exposure followed by acute onset of dry cough and progressive dyspnea on exertion in addition to systemic signs and symptoms ( conjunctivitis, dermatitis, laryngotracheobronchitis ). - Further radiographic finding occur with 1 to 3 weeks of exposure. In chronic beryllium disease, the sign and symptoms are present for at least a year and clinical presentation can be varied from asymptomatic to dry cough, progressive dyspnea, fatigue, and night sweats. Bal BeLPT is highly sensitive and specific, helping to distinguish chronic beryllium disease from sarcoidosis and another form of diffuse pulmonary disease. - Ultimately, this process leads to restrictive lung disease, a decreased diffusion capacity. ## Complications Rarely, one can get granulomas in other organs including the liver. ## Prognosis Acute beryllium disease can be fatal but the prognosis is usually excellent unless progression to chronic beryllium disease occurs. Chronic beryllium disease often results in progressive loss of respiratory function. Early abnormalities include airflow obstruction and decreased oxygenation on ABG at rest and during exercise testing. Decreased diffusing capacity for carbon monoxide ( DLco) and restriction appear later pulmonary hypertension and right ventricular failure develop in about 10 % case, which death due to cor pulmonale. Mortality rates range from 6 to 35 percent.The variability of mortality depend duration of beryllium exposure after development of chronic beryllium disorder disease, individual variation and duration of follow up. ## History and Symptoms - History of beryllium exposure - Positive blood or bronchoalveolar lavage ( beryllium lymphocyte proliferation test BeLPT - Cough - Shortness of breath - Chest pain - Arthralgia - Weight loss - Fever - The onset of symptoms can range from weeks up to tens of years from the initial exposure. In some individuals a single exposure can cause berylliosis. ## Laboratory Test - Blood beryllium lymphocyte proliferation test ( BeLPT ) - High resolution computed tomography ( HRCT ) - Bronchoalveolar lavage - Tissue biopsy - Pulmonary function test - Chest X ray - Chest X- ray may be normal or show diffuse infiltrate that can be nodular,reticular or have a hazy ground - glass appearance, often with hilar adenopathy resembling the pattern seen in sarcoidosis. - A miliary pattern also occur in high resolution CT is more sensitive than X-ray. - Biopsy proven disease occurrence even in people with normal imaging test result. # Treatment - There is no cure for CBD the goal is reducing symptoms and slow progression of the disease. - All patient with CBD should be removed from further exposure to beryllium decrease the progression of the disease. - There is no specific treatment for CBD but drug of choice is glucocorticoid therapy. - Initial dose is 0.5 to 0.6 mg/k of prednisone for 6 to 12 weeks. - Methotrexate is also used if patient not respond to glucocorticoid or has severe side effects from glucocorticoid. - Once diagnosed and successfully treated, patients with CBD need long term followed-up with pulmonologist to monitor lung function. - In acute beryllium disease patient put on mechanical ventilation. - In chronic beryllium disease, supplemental oxygen,pulmonary rehabilitation and treatment for right ventricular failure. - In end stage chronic beryllium disease sometime lung transplantation. # Prevention - Industrial dust suppression is the basis for preventing beryllium exposure. Exposure must be limited to a level that is as low as reasonably achievable 0.2 micrograms per cubic meter of air. - Average over 8 hours and limited short term exposure to 2 micrograms per cubic meter of air over a 15 minutes sampling period. - Medical surveillance, using blood BeLPT and chest X-ray is recommended for all exposed workers including those indirect contact. Both acute and chronic diseases must be promptly recognized and affected workers removed from further beryllium exposure.	Berylliosis Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2] Synonyms and keywords: Chronic beryllium disorder; CBD # Overview Berylliosis or chronic beryllium disorder (CBD) is a chronic allergic-type lung response and chronic lung disease caused by exposure to beryllium and its compounds. The condition is incurable but symptoms can be treated. Berylliosis was first discovered by Dr. Harriet Hardy, an American pathologist, in 1945 following an outbreak of respiratory illnesses affecting nearby factory workers. Berylliosis may be classified as a rare disorder and an occupational disease. Exposure to beryllium can cause cell-mediated immunity. In each subsequent exposure macrophages and CD4+ helper T - lymphocytes accumulation in the lungs. As a result macrophages, CD4+ helper T - lymphocytes and plasma cells accumulate to form noncaseating granulomas that cause fibrosis. Granulomas are seen in other chronic diseases, such as tuberculosis, sarcoidosis, and it can occasionally be hard to distinguish berylliosis from these disorders. # Historical Perspective - Berylliosis was first discovered by Dr. Harriet Hardy, an American pathologist, in 1945 following an outbreak of respiratory illnesses affecting nearby factory workers.[1][2] - In 1946, Hardy established the National Beryllium Registry at the Massachusetts General Hospital.[2] # Classification - There is no formal classification system established for berylliosis. - Berylliosis may be classified as a rare disorder and an occupational disease.[3][4] # Pathophysiology - Exposure to beryllium can cause cell-mediated immunity, which can sensitize the T cells to beryllium. - In each subsequent exposure macrophage and CD4+ helper T - lymphocytes accumulation in the lungs. - As a result macrophages, CD4+ T lymphocyte and plasma cell accumulate to form noncaseating granulomas that cause fibrosis.[5] - Beryllium is presented to CD4+ T cell by antigen-presenting cells, principally in HLA-DP molecules. T cells in the blood lungs or other organs, in turn, recognize the beryllium, proliferate and form T cell clones. These cause the release of proinflammatory cytokines. such as tumor necrosis factor-alpha, IL-2 and interferon-gamma. These cytokines amplify the immune response, as result formation of mononuclear cell infiltrates and noncaseating granulomas in target organs where beryllium has deposited. - On average about 2 to 6 % of beryllium exposed people develop beryllium sensitized ( defined by positive blood lymphocyte proliferation salt in vitro ) with most progressing to disease. In certain high-risk groups such as beryllium metal and alloy machinists, chronic beryllium disease prevalence is > 17 % workers with bystander exposures, such as secretaries and security guards, also develop sensitization and disease but at lower rates. The typical pathologic consequence is a diffuse pulmonary, hilar, and mediastinal lymph node granulomatous reaction that is histologically indistinguishable from sarcoidosis. - Early granuloma formation with mononuclear and giant cells can also occur. - Many lymphocytes are found when the cell is washed from the lungs ( bronchoalveolar lavage BAL during bronchoscopy. - These T cells proliferate when exposed to beryllium in vitro, much as the blood cells do ( a test called beryllium lymphocyte proliferation test BeLPT ). # Causes - Chronic exposure to beryllium - Genetic predisposition ( Mutation at the HL-A DPB1 Glu69 position increase the prevalence of beryllium sensitization.[6] # Differentiating Berylliosis from other Diseases Granulomas are seen in other chronic diseases, such as tuberculosis, sarcoidosis, and it can occasionally be hard to distinguish berylliosis from these disorders. # Risk Factors - Extended exposure with beryllium - Genetic predisposition ( Mutation at the HL-A DPB1 Glu69 position increase the prevalence of beryllium sensitization. # Natural History, Complications, and Prognosis ## Natural History - Patients with chronic beryllium disease often have dyspnea, cough, weight loss, and a variable chest X-ray pattern, typically showing nodular opacities in the mid and upper lung zones, frequently with hilar and mediastinal adenopathy. - Patients complain of insidious and progressive exertional dyspnea, cough, chest pain, weight loss, night sweats, and fatigue. Symptoms may develop within months of first exposure or more than 30 years after exposure and some people remain asymptomatic. - Acute beryllium disease is distinguished from chronic disease based on the history of the very high level of exposure followed by acute onset of dry cough and progressive dyspnea on exertion in addition to systemic signs and symptoms ( conjunctivitis, dermatitis, laryngotracheobronchitis ). - Further radiographic finding occur with 1 to 3 weeks of exposure. In chronic beryllium disease, the sign and symptoms are present for at least a year and clinical presentation can be varied from asymptomatic to dry cough, progressive dyspnea, fatigue, and night sweats. Bal BeLPT is highly sensitive and specific, helping to distinguish chronic beryllium disease from sarcoidosis and another form of diffuse pulmonary disease. - Ultimately, this process leads to restrictive lung disease, a decreased diffusion capacity. ## Complications Rarely, one can get granulomas in other organs including the liver. ## Prognosis Acute beryllium disease can be fatal but the prognosis is usually excellent unless progression to chronic beryllium disease occurs. Chronic beryllium disease often results in progressive loss of respiratory function. Early abnormalities include airflow obstruction and decreased oxygenation on ABG at rest and during exercise testing. Decreased diffusing capacity for carbon monoxide ( DLco) and restriction appear later pulmonary hypertension and right ventricular failure develop in about 10 % case, which death due to cor pulmonale. Mortality rates range from 6 to 35 percent.The variability of mortality depend duration of beryllium exposure after development of chronic beryllium disorder disease, individual variation and duration of follow up.[7][8] ## History and Symptoms - History of beryllium exposure - Positive blood or bronchoalveolar lavage ( beryllium lymphocyte proliferation test BeLPT - Cough - Shortness of breath - Chest pain - Arthralgia - Weight loss - Fever - The onset of symptoms can range from weeks up to tens of years from the initial exposure. In some individuals a single exposure can cause berylliosis. ## Laboratory Test - Blood beryllium lymphocyte proliferation test ( BeLPT )[9] - High resolution computed tomography ( HRCT ) - Bronchoalveolar lavage - Tissue biopsy - Pulmonary function test - Chest X ray[10] - Chest X- ray may be normal or show diffuse infiltrate that can be nodular,reticular or have a hazy ground - glass appearance, often with hilar adenopathy resembling the pattern seen in sarcoidosis. - A miliary pattern also occur in high resolution CT is more sensitive than X-ray. - Biopsy proven disease occurrence even in people with normal imaging test result. # Treatment - There is no cure for CBD the goal is reducing symptoms and slow progression of the disease. - All patient with CBD should be removed from further exposure to beryllium decrease the progression of the disease.[11] - There is no specific treatment for CBD but drug of choice is glucocorticoid therapy. - Initial dose is 0.5 to 0.6 mg/k of prednisone for 6 to 12 weeks. - Methotrexate is also used if patient not respond to glucocorticoid or has severe side effects from glucocorticoid. - Once diagnosed and successfully treated, patients with CBD need long term followed-up with pulmonologist to monitor lung function.[12] - In acute beryllium disease patient put on mechanical ventilation. - In chronic beryllium disease, supplemental oxygen,pulmonary rehabilitation and treatment for right ventricular failure. - In end stage chronic beryllium disease sometime lung transplantation. # Prevention - Industrial dust suppression is the basis for preventing beryllium exposure. Exposure must be limited to a level that is as low as reasonably achievable 0.2 micrograms per cubic meter of air. - Average over 8 hours and limited short term exposure to 2 micrograms per cubic meter of air over a 15 minutes sampling period. - Medical surveillance, using blood BeLPT and chest X-ray is recommended for all exposed workers including those indirect contact. Both acute and chronic diseases must be promptly recognized and affected workers removed from further beryllium exposure.	https://www.wikidoc.org/index.php/Berylliosis
68ec7217be3c8e7de0e9b2224ff246af315fbabb	wikidoc	Beta-glucan	Beta-glucan β-Glucans (or beta-glucans) are polysaccharides occurring in the bran of cereal grains, the cell wall of baker's yeast, certain types of fungi, and many kinds of mushrooms. The cereal based beta glucans occur most abundantly in barley and oats and to a much lesser degree in rye and wheat. They are useful in human nutrition as texturing agents and as soluble fiber supplements, but problematic in brewing as excessive levels make the wort too viscous. An insoluble (1,3/1,6) beta glucan derived from baker's yeast has a different molecular structure than that of its soluble (1,3/1,4) counterparts and has a greater biological activity due to its structural "branching". Yeast derived beta glucans are notable for their immunomodulatory function. The differences between soluble and insoluble beta glucans are significant in regards to application, mode of action, and overall biological activity. # Overview Glucans are polysaccharides that only contain glucose as structural components. Beta 1, 3-D glucans are chains of D-glucose molecules, with the six-sided D-glucose rings connected at the 1 and 3 positions. Smaller side chains branch off the 1,3 polysaccharide “backbone.” The most active form of Beta 1, 3-D glucans are apparently those that contain 1,6 side-chains branching off from the longer beta-1,3 glucan backbone. These are referred to as beta-1,3/1,6 glucan. Some researchers have suggested that it is the frequency, location, and length of the side-chains rather than the backbone of beta glucans that determine their immune system activity. Another variable is the fact that some of these compounds exist as single strand chains, while the backbones of other beta-1,3 glucans exist as double or triple stranded helix chains. In some cases, proteins linked to the beta-1,3 glucan backbone may also be involved in providing therapeutic activity. Although these compounds have exciting potential for enhancement of the immune system, it must be emphasized that this research is in its infancy, and there are differing opinions on which molecular weight, shape, structure, and source of beta-1, 3 glucans provide the greatest therapeutic benefit. One of the most common sources of Beta 1, 3-D glucan is derived from the cell wall of baker’s yeast (Saccharomyces cerevisiae). However, beta-1,3 glucans are also extracted from the bran of some grains such as oats and barley. The Beta 1, 3-D glucans from yeast are often insoluble whereas those extracted from grains tend to be soluble. Other sources include some types of seaweed , and various species of mushrooms such as Reishi, Shiitake, and Maitake. Beta 1, 3-D glucans are being referred to as biological response modifiers because of their ability to activate the immune system. However, it should be noted that the activity of Beta 1, 3-D glucan is different from agents that stimulate the immune system. Agents that stimulate the immune system can push the system to over-stimulation, and hence are contraindicated in individuals with autoimmune diseases, allergies, or yeast infections. Beta 1, 3-D glucans seem to make the immune system work better without becoming overactive. They accomplish this by activating phagocytes, which are immune system cells whose function is to trap and destroy foreign substances in our bodies such as bacteria, viruses, fungi, and parasites. In addition to enhancing the activity of phagocytes, beta-1,3 glucans also reportedly lower elevated levels of LDL cholesterol, aid in wound healing, help prevent infections, enhance NK cell function, and help in the prevention and treatment of cancer. # Clinical Applications (conclusions of investigators) · Cancer: β-Glucan has been used as an immunoadjuvant therapy for cancer since 1980, primarily in Japan. Numerous studies report that beta-1, 3 glucan has anti-tumor and anti-cancer activity. In one study, intralesional administration of beta-1,3 glucans resulted in rapid tumor shrinkage. In another study with mice, beta 1,3 glucan in conjunction with interferon gamma inhibited both the establishment of tumors and liver metastasis. In some studies, beta-1,3 glucans enhanced the effects of chemotherapy. In studies on bladder cancer with mice, administration of cyclophosphamide, in conjunction with beta-1,3 glucans derived from yeast resulted in reduced mortality. In human patients with advanced gastric or colorectal cancer, the administration of beta-1,3 glucans derived from shiitake mushrooms, in conjunction with chemotherapy resulted in prolonged survival times compared to a control group receiving identical chemotherapy. Preclinical studies have shown that a soluble yeast β-glucan product, Imprime PGG, when used in combination with certain monoclonal antibodies or cancer vaccines, offers significant improvements in long-term survival versus monoclonal antibodies alone. This benefit, however, does not result from Betafectin enhancing the specific killing action of the antibody. The anti-tumor activity is caused by a unique killing mechanism that involves neutrophils that are primed with Betafectin and which are not normally involved in the fight against cancer. Recent research by Hong et al, demonstrates that this mechanism of action is effective against a broad range of cancers when used in combination with specific monoclonal antibodies that activate or cause complement to be bound to the tumor. The complement enables these primed neutrophils to find and bind to the tumor, which facilitates killing. Innate immune cells are the body’s first line of defense and circulate throughout the body engaging in an immune response against “foreign” challenges (bacteria, fungus, parasites). Typically, neutrophils are not involved in the destruction of cancerous tissue because these immune cells view cancer as "self" rather than foreign or "non-self." Current cancer immunotherapies involve monoclonal antibodies and vaccines, which stimulate the acquired immune response, but do nothing to change the innate immune system's view of cancer as "self." As a result the monoclonal antibodies alone do not engage or initiate the potential killing ability of the innate immune system, which is our primary mechanism of defense against bacteria and yeast (fungal) infections. Dr. Gordon Ross and Dr. Vaclav Vetvicka, respected immunologists and cancer researchers at the University of Louisville, discovered that a receptor on the surface of these innate immune cells called Complement Receptor 3 ( CR3 or CD11b/CD18) was responsible for binding to fungi or yeast, allowing the immune cells to recognize them as "non-self." This receptor is a dual occupancy receptor in that it has two binding sites. The first site is responsible for binding to a type of complement, a soluble blood protein, known as C3 (or iC3b). C3 becomes attached to pathogens that specific antibodies have targeted and opsonized. The second site of this receptor binds to a carbohydrate on yeast or fungal cells that allows the innate immune cell to recognize yeast and fungi as being "non-self ”. Both of these receptor sites must be simultaneously occupied to trigger the innate immune cell to destroy the yeast or fungi. Two obstacles prevent neutrophils from using this mechanism of action against cancer. First, the body usually does not generate enough natural antibodies to bind to the tumor, and this prevents the activation and attachment of (or “fixing”) complement to the surface of the cancer cell. Therefore, neutrophils don’t bind to cancer via the first receptor site of CR3. The second obstacle is that even when the natural antibody response is supplemented with monoclonal antibodies that fix complement and binding occurs at the first site, tumors do not contain a foreign carbohydrate serving as “second signal” on their surface that allows neutrophils to recognize the cancer as "non-self “. Dr. Ross discovered that a bio-processed fragment of Imprime PGG specifically binds to the second CR3 receptor site on neutrophils. When neutrophils bind to tumors, the Betafectin allows them to “see” cancer as if it were a yeast or fungal pathogen and provide the “second signal” to trigger killing. In summary, Betafectin engages neutrophils in the fight against cancer, dramatically and synergistically enhancing the effectiveness of complement activating monoclonal antibodies and vaccines through a different killing mechanism. Multinational research has successfully demonstrated that the oral form of yeast Beta 1,3-D glucan has similar protective effects as the injected version, including defense against infectious diseases and cancer. Recently, orally-delivered glucan was found to significantly increase proliferation and activation of monocytes in peripheral blood of patients with advanced breast cancer. The technology has wide applicability for cancer therapy. Each form of cancerous tumor cell has specific antigens on the cell surface, some of which are common to other types of cancer. (Example: Mucin 1 is present on about 70% of all types of cancer cells) Different immunotherapies target different antigens for binding monoclonal antibodies to tumor cells. This has resulted in the development of hundreds of monoclonal antibodies, many targeting a different specific antigen on cancer cells. In research studies, Betafectin has improved the effectiveness of all complement-activating monoclonal antibodies tested including breast, liver and lung cancer (company data). The magnitude of success varies based on the specific monoclonal antibody used and the type of cancer. · Prevention of infection: To date there have been numerous studies and clinical trials conducted with the soluble yeast β-glucan and the whole glucan particulate. These studies have ranged from the impact of β-glucan on post-surgical nosocomial infections to the role of yeast β-glucans in treating anthrax infections. Post-surgical infections are a serious challenge following major surgery with estimates of 25-27% infection rates post-surgery. Alpha-Beta Technologies conducted a series of human clinical trials in the 1990’s to evaluate the impact of β-glucan therapy for controlling infections in high-risk surgical patients. In the initial trial 34 patients were randomly (double-blind, placebo-controlled) assigned to treatment or placebo groups. Patients that received the PGG-glucan had significantly fewer infectious complications than the placebo group (1.4 infections per infected patient for PGG-glucan group vs. 3.4 infections per infected patient for the placebo group). Additional data from the clinical trial revealed that there was decreased use of intravenous antibiotics and shorter stays in the intensive care unit for the patients receiving PGG-glucan vs. patients receiving the placebo. A subsequent human clinical trial further studied the impact of β-glucan for reducing the incidence of infection with high-risk surgical patients. The authors found a similar result with a dose-response trend (higher dose provided greater reduction in infectious occurrences than low doses). In the human clinical trial 67 patients were randomized and received either a placebo or a dose of 0.1, 0.5, 1.0 or 2.0 mg PGG-Glucan per KG of body weight. Serious infections occurred in four patients that received the placebo, three patients that received the low dose (0.1 mg/KG) of PGG-Glucan and only one infection was observed at the highest dose of 2.0 mg/KG of PGG-Glucan. The results of a phase III human clinical trial showed that PGG-Glucan therapy reduced serious post-operative infections by 39% after high-risk noncolorectal operations. This study was conducted in patients that were already as high-risk because of the type of surgery and were more susceptible to infections and other complications. At this point in the development of an injectable form of b-glucan (Betafectin PGG-glucan) most scientists already concluded that yeast-derived b-glucan promoted phagocytosis and subsequent killing of pathogenic bacteria. A phase III clinical trial was proposed and conducted at thirty-nine medical centers in the U.S. involving 1,249 subjects stratified according to colorectal or non-colorectal surgical patients. The PGG-glucan was given once pre-operatively and three times post-operative at 0, 0.5 or 1.0 mg/kg body weight. The measured outcome was serious infection or death of the subjects within 30 days post-surgery. The results of the phase III human clinical trial showed that injectable PGG-Glucan therapy reduced serious post-operative infections by 39% after high-risk noncolorectal operations. There have been studies with humans and animal models that further support the efficacy of β-glucan in combating various infectious diseases. One human study demonstrated that consumption of oral whole glucan particles increased the ability of immune cells to consume a bacterial challenge (phagocytosis). The total number of phagocytic cells and the efficiency of phagocytosis in healthy human study participants increased while consuming a commercial particulate yeast β-glucan. This study demonstrated the potential for yeast β-glucan to increase the reaction rate of the immune system to infectious challenges. The study concluded that oral consumption of whole glucan particles represented a good enhancer of natural immunity. Anthrax is a disease that cannot be tested in human studies for obvious reasons. In a study conducted by the Canadian Department of Defense, Dr. Kournikakis showed that orally administered yeast β-glucan given with or without antibiotics protected mice against anthrax infection. A dose of antibiotics along with oral whole glucan particles (2 mg/KG body weight or 20 mg/KG body weight) for eight days prior to infection with Bacillus anthracis protected mice against anthrax infection over the 10-day post-exposure test period. Mice treated with antibiotic alone did not survive. A second experiment was conducted to investigate the effect of yeast β-glucan orally consumed after exposure of mice to B. anthracis. The results were similar to the previous experiment with an 80-90% survival rate for mice treated with β-glucan, but only 30% for the control group after 10-days of exposure. The hopeful inference is that similar results would be observed with humans. Since there are many commercial products on the market called “glucan”, there is much confusion among consumers as to which type(s) may be the most effective. One of the most comprehensive published studies to date showed Glucan #300, a highly purified yeast glucan, to be “the biologically most relevant immunomodulator” out of a wide ranging group. · Radiation exposure: β-glucan is a well-known biological response modifier (BRM) isolated from the yeast cell wall polysaccharides and is made up entirely of glucose β(1,3)-linked together in linear chains with variable frequency of β(1,6)-linked side chains. Specific hematopoietic activity was first demonstrated with β-glucan in the mid-1980s in an analogous manner as granulocyte monocyte–colony stimulating factor (GM-CSF).Research was carried out initially with particulate β-glucan and later with soluble β-glucans, all of which were administered intravenously to mice.Mice exposed to 500-900 cGy (500-900 mrads) of gamma radiation exhibited a significantly enhanced recovery of blood leukocyte, platelet and red blood cell counts when given i.v. β-glucan. Other reports showed that β-glucan could reverse the myelo-suppression produced with chemotherapeutic drugs such as fluorouracil, carboplatinum or cyclophosphamide. Moreover, the anti-infective activity of β-glucan combined with its hematopoiesis-stimulating activity resulted in enhanced survival of mice receiving a lethal dose of 900-1200 cGy of radiation. In vitro studies showed that β-glucan could enhance granulocyte and megakaryocyte colony formation by hematopoietic stem progenitor cells when used in combination with GM-CSF and interleukin-3 (IL-3), respectively. Original studies delivered glucan almost entirely by injection. Later, numerous studies tried to evaluate the possibility that glucan can be delivered orally without compromising its biological activities,opening the oral route of administration as a more pleasant alternative. A study by Allendorf et al. clearly demonstrated that oral Beta glucan had hematopoietic effects analogous to Beta glucan administered by i.v. methods, work of Vetvicka’s group showed the mechanisms of the glucan transfer through the gastrointestinal tract. Allendorf et al. demonstrated that orally administered whole glucan particulate functions to accelerate hematopoiesis following irradiation in an analogous manner as i.v. administered β-glucan. Experiments by Cramer et al. or Vetvicka clearly demonstrated that oral β-glucan stimulates hematopoiesis in radiation-treated mice. Currently, there is renewed interest in the potential usefulness of β-glucan as a radioprotective drug for chemotherapy, radiation therapy and nuclear emergencies, particularly because glucan can be used not only as a treatment, but also as a prophylactic. · Septic shock: One of the mechanisms of the immune-enhancing ability of yeast β-glucan is its ability to prime leukocytes to more easily locate and kill non-self cells including bacteria. Early research by Onderdonk et al. investigated the ability of yeast b-glucan to reduce septic infections using in vivo models. Onderdonk et al. found that mice challenged with E. coli or S. aureus bacteria were protected against septic infections when they were injected with PGG-glucan 4–6 hours prior to infection. Additional research further supports that yeast β-glucan reduces septic shock by killing bacteria present in blood. Work by Kernodle et al. demonstrated that preventative dosing of yeast β-glucan prior to infection with S. aureus prevented sepsis in a guinea pig model. Research on the use of yeast β-glucan immunomodulators as a means of treating and preventing bacterial sepsis is well documented. Recent reports on glucan and sepsis revealed another possible mechanism - glucan protects against oxidative organ injury. · Surgery: There have been numerous studies and clinical trials conducted with the soluble yeast β-glucan particle and the whole glucan particle. Immunomodulators that enhance macrophage function have been shown to be beneficial in human, as well as, animal models. One such study that looked at this correlation examined wound tensile strength and collagen biosynthesis. Positive effects were observed. In a prospective, randomized, double-blind study, 38 trauma patients received an I.V. of a soluble yeast derived glucan for 7 days or placebo. The total mortality rate was significantly less in the glucan group (0% vs. 29%). There was also a decrease in septic morbidity (9.5% vs. 49%). Further such trials to evaluate Biological Response Modifiers (BRM’s) in trauma patients are indicated. Yeast derived beta glucan significantly enhanced phagocytic activity in control and operated mice. In an experimental C. albicans model, mice had induced sepsis along with a midline laparotomy. The non-operated mice on glucan had a 100% survival vs. 73% in the surgical group. Detrimental effects of surgery on survival of C. albicans infection manifested in a 47% survival in the non-surgical vs a 20% survival in the surgery-infected group. The nonspecific immunostimulation of yeast derived glucan appears to have significant potential as a treatment strategy against post-operative infections. In a post splenectomy mouse model, glucan increased survival vs. controls via 75% as opposed to 27%, Severe sepsis enhances risks in both adult and pediatric patients. These works suggest another option beyond prophylactic antibiotics and bacterial vaccines that often have limited success against morbidity and mortality. · Wound healing: Macrophage activity is known to play a key role in wound healing from surgery or trauma. In both animal and human studies, therapy with Beta glucan has provided improvements such as fewer infections, reduced mortality, and stronger tensile strength of scar tissue. · Allergic rhinitis: This disease is caused by an IgE-mediated allergic inflammation of the nasal mucosa. Orally-administered yeast-glucan decreased levels of IL-4 and IL-5 cytokines responsible for the clinical manifestation of this disease, while increased the levels of IL-12. Based on these studies, glucan may have a role as an adjunct to standard treatment in patients with allergic diseases. · Arthritis: Using paramagnetic resonance spectroscopy, yeast-derived glucan was found to cause decline in oxidative tissue damage during the progress of arthritic diseases, suggesting the role in treatment of arthritis. · Additional functions: Influence of certain cereals (barley, oats) and edible mushrooms upon decrease of levels of serum cholesterol and liver low-density lipoproteins, leading to lowering of arteriosclerosis and heart disease hazards, is also mediated by b-glucan. It is known that cereals, mushrooms and yeast facilitate bowel motility and can be used in amelioration of intestinal problems, particularly obstipation. Non-digestible b-glucans, forming a remarkable portion of these materials, are also able to modulate mucosal immunity of the intestinal tract. In the central nervous system, β-glucans activate microglial cells. These cells act as scavengers of the brain cell debris and play a positive role in Alzheimer’s disease, AIDS, ischemia injury and multiple sclerosis. # Functions in the Body Beta-1,3 glucans improve the body’s immune system defense against foreign invaders by enhancing the ability of macrophages, neutrophils and natural killer cells to respond to and fight a wide range of challenges such as bacteria, viruses, fungi, and parasites. Symptoms and Causes of Deficiency: Beta-1, 3 glucans do not occur naturally in humans, hence no deficiency condition exists. Absorption: For best results, Beta 1, 3-D glucan should be taken on an empty stomach. Enterocytes reportedly facilitate the transportation of beta-1, 3 glucans and similar compounds across the intestinal cell wall into the lymph where they begin to interact with macrophages to activate immune function. Radiolabeled studies have verified that both small and large fragments of beta glucans are found in the serum, which indicates they are absorbed from the intestinal tract. M cells within the Peyer’s Patches physically transport the insoluble whole glucan particles into the GALT. Dietary Sources: Although beta-1 3 glucans occur in baker’s yeast, seaweed, grains such as oats and barley, and numerous mushrooms, they are not readily usable in their natural state. The indigestible cell walls of these substances must be processed in order to free up the beta-1, 3 glucans and make them available for useful purposes. # Yeast Derived Beta Glucan Yeast Beta 1, 3-D Glucan These are sometimes seen as synonyms: β-Glucan \| (1,3/1,6)-β-D-glucan \| whole glucan particulate \| 1,3/1,6 glucan \| (1→3,1→6) glucan Dosage Range: From 40 mg to 3000 mg daily. Most Common Dosage: Variable, depending upon body weight and whether it is being used for maintenance or an acute condition. As a dietary supplement (maintenance use), the most common dose range has been reported as 40-500 mg per day. When the dosage is reported on a kilogram of body weight basis the dose range is 2-6 mg/kg. If the particulate glucan is being self-administered for an acute condition, a higher dose of 500-3000 mg/day is typically administered. Active Forms: Immune-enhancing activity has been reported for Beta 1, 3-D glucan with 1,6 glucan side chains, which are derived from yeasts. Many varieties of mushrooms have also been reported that have a Beta-1,3/1,4 glucan linkage, similar to glucans from oats and barley. Dosage Forms: As a dietary supplement the most common forms are capsules and tablets. Additional uses also include topical creams and injectables. Toxicities, Cautions, and Contraindications: Beta 1, 3-D glucan has been recognized as GRAS and the FDA has accepted notification of the GRAS affirmation. The specific conditions of manufacture, safety data and product specifications apply only to the Beta 1, 3-D glucan produced by a process as defined in the GRAS dossier and FDA Notification. Although side effects are very rare, occasionally an allergic reaction is reported. All sufficiently purified polysaccharidic immunomodulators distinguish themselves by very low toxicity (e.g., for mouse lentinan has LD50 > 1600 mg/kg). Potential Interactions: Drug/Nutrient Interactions: None known Nutrient/Nutrient Interactions: None known	Beta-glucan Template:Cleanup β-Glucans (or beta-glucans) are polysaccharides occurring in the bran of cereal grains, the cell wall of baker's yeast, certain types of fungi, and many kinds of mushrooms. The cereal based beta glucans occur most abundantly in barley and oats and to a much lesser degree in rye and wheat. They are useful in human nutrition as texturing agents and as soluble fiber supplements, but problematic in brewing as excessive levels make the wort too viscous. An insoluble (1,3/1,6) beta glucan derived from baker's yeast has a different molecular structure than that of its soluble (1,3/1,4) counterparts and has a greater biological activity due to its structural "branching". Yeast derived beta glucans are notable for their immunomodulatory function. The differences between soluble and insoluble beta glucans are significant in regards to application, mode of action, and overall biological activity. # Overview Glucans are polysaccharides that only contain glucose as structural components. Beta 1, 3-D glucans are chains of D-glucose molecules, with the six-sided D-glucose rings connected at the 1 and 3 positions. Smaller side chains branch off the 1,3 polysaccharide “backbone.” The most active form of Beta 1, 3-D glucans are apparently those that contain 1,6 side-chains branching off from the longer beta-1,3 glucan backbone. These are referred to as beta-1,3/1,6 glucan. Some researchers have suggested that it is the frequency, location, and length of the side-chains rather than the backbone of beta glucans that determine their immune system activity. Another variable is the fact that some of these compounds exist as single strand chains, while the backbones of other beta-1,3 glucans exist as double or triple stranded helix chains. In some cases, proteins linked to the beta-1,3 glucan backbone may also be involved in providing therapeutic activity. Although these compounds have exciting potential for enhancement of the immune system, it must be emphasized that this research is in its infancy, and there are differing opinions on which molecular weight, shape, structure, and source of beta-1, 3 glucans provide the greatest therapeutic benefit. One of the most common sources of Beta 1, 3-D glucan is derived from the cell wall of baker’s yeast (Saccharomyces cerevisiae). However, beta-1,3 glucans are also extracted from the bran of some grains such as oats and barley. The Beta 1, 3-D glucans from yeast are often insoluble whereas those extracted from grains tend to be soluble. Other sources include some types of seaweed [1], and various species of mushrooms such as Reishi, Shiitake, and Maitake.[2] Beta 1, 3-D glucans are being referred to as biological response modifiers because of their ability to activate the immune system.[3] However, it should be noted that the activity of Beta 1, 3-D glucan is different from agents that stimulate the immune system. Agents that stimulate the immune system can push the system to over-stimulation, and hence are contraindicated in individuals with autoimmune diseases, allergies, or yeast infections. Beta 1, 3-D glucans seem to make the immune system work better without becoming overactive. They accomplish this by activating phagocytes, which are immune system cells whose function is to trap and destroy foreign substances in our bodies such as bacteria, viruses, fungi, and parasites.[4] In addition to enhancing the activity of phagocytes, beta-1,3 glucans also reportedly lower elevated levels of LDL cholesterol, aid in wound healing, help prevent infections, enhance NK cell function, and help in the prevention and treatment of cancer. # Clinical Applications (conclusions of investigators) · Cancer: β-Glucan has been used as an immunoadjuvant therapy for cancer since 1980, primarily in Japan. Numerous studies report that beta-1, 3 glucan has anti-tumor and anti-cancer activity.[5] [6] In one study, intralesional administration of beta-1,3 glucans resulted in rapid tumor shrinkage.[7] In another study with mice, beta 1,3 glucan in conjunction with interferon gamma inhibited both the establishment of tumors and liver metastasis.[8] In some studies, beta-1,3 glucans enhanced the effects of chemotherapy. In studies on bladder cancer with mice, administration of cyclophosphamide, in conjunction with beta-1,3 glucans derived from yeast resulted in reduced mortality.[9] In human patients with advanced gastric or colorectal cancer, the administration of beta-1,3 glucans derived from shiitake mushrooms, in conjunction with chemotherapy resulted in prolonged survival times compared to a control group receiving identical chemotherapy.[10] Preclinical studies have shown that a soluble yeast β-glucan product, Imprime PGG, when used in combination with certain monoclonal antibodies or cancer vaccines, offers significant improvements in long-term survival versus monoclonal antibodies alone.[11] This benefit, however, does not result from Betafectin enhancing the specific killing action of the antibody. The anti-tumor activity is caused by a unique killing mechanism that involves neutrophils that are primed with Betafectin and which are not normally involved in the fight against cancer.[11][12] Recent research by Hong et al, demonstrates that this mechanism of action is effective against a broad range of cancers when used in combination with specific monoclonal antibodies that activate or cause complement to be bound to the tumor.[13] The complement enables these primed neutrophils to find and bind to the tumor, which facilitates killing. Innate immune cells are the body’s first line of defense and circulate throughout the body engaging in an immune response against “foreign” challenges (bacteria, fungus, parasites). Typically, neutrophils are not involved in the destruction of cancerous tissue because these immune cells view cancer as "self" rather than foreign or "non-self." Current cancer immunotherapies involve monoclonal antibodies and vaccines, which stimulate the acquired immune response, but do nothing to change the innate immune system's view of cancer as "self." As a result the monoclonal antibodies alone do not engage or initiate the potential killing ability of the innate immune system, which is our primary mechanism of defense against bacteria and yeast (fungal) infections. Dr. Gordon Ross and Dr. Vaclav Vetvicka, respected immunologists and cancer researchers at the University of Louisville, discovered that a receptor on the surface of these innate immune cells called Complement Receptor 3 ( CR3 or CD11b/CD18) was responsible for binding to fungi or yeast, allowing the immune cells to recognize them as "non-self."[11] This receptor is a dual occupancy receptor in that it has two binding sites. The first site is responsible for binding to a type of complement, a soluble blood protein, known as C3 (or iC3b). C3 becomes attached to pathogens that specific antibodies have targeted and opsonized. The second site of this receptor binds to a carbohydrate on yeast or fungal cells that allows the innate immune cell to recognize yeast and fungi as being "non-self ”.[12][14] Both of these receptor sites must be simultaneously occupied to trigger the innate immune cell to destroy the yeast or fungi. Two obstacles prevent neutrophils from using this mechanism of action against cancer. First, the body usually does not generate enough natural antibodies to bind to the tumor, and this prevents the activation and attachment of (or “fixing”) complement to the surface of the cancer cell. Therefore, neutrophils don’t bind to cancer via the first receptor site of CR3. The second obstacle is that even when the natural antibody response is supplemented with monoclonal antibodies that fix complement and binding occurs at the first site, tumors do not contain a foreign carbohydrate serving as “second signal” on their surface that allows neutrophils to recognize the cancer as "non-self “.[12][15] Dr. Ross discovered that a bio-processed fragment of Imprime PGG specifically binds to the second CR3 receptor site on neutrophils. When neutrophils bind to tumors, the Betafectin allows them to “see” cancer as if it were a yeast or fungal pathogen and provide the “second signal” to trigger killing. In summary, Betafectin engages neutrophils in the fight against cancer, dramatically and synergistically enhancing the effectiveness of complement activating monoclonal antibodies and vaccines through a different killing mechanism. Multinational research has successfully demonstrated that the oral form of yeast Beta 1,3-D glucan has similar protective effects as the injected version, including defense against infectious diseases and cancer.[16][17][18][19][20] Recently, orally-delivered glucan was found to significantly increase proliferation and activation of monocytes in peripheral blood of patients with advanced breast cancer.[21] The technology has wide applicability for cancer therapy. Each form of cancerous tumor cell has specific antigens on the cell surface, some of which are common to other types of cancer. (Example: Mucin 1 is present on about 70% of all types of cancer cells) Different immunotherapies target different antigens for binding monoclonal antibodies to tumor cells. This has resulted in the development of hundreds of monoclonal antibodies, many targeting a different specific antigen on cancer cells. In research studies, Betafectin has improved the effectiveness of all complement-activating monoclonal antibodies tested including breast, liver and lung cancer (company data). The magnitude of success varies based on the specific monoclonal antibody used and the type of cancer. · Prevention of infection: To date there have been numerous studies and clinical trials conducted with the soluble yeast β-glucan and the whole glucan particulate. These studies have ranged from the impact of β-glucan on post-surgical nosocomial infections to the role of yeast β-glucans in treating anthrax infections. Post-surgical infections are a serious challenge following major surgery with estimates of 25-27% infection rates post-surgery.[22] Alpha-Beta Technologies conducted a series of human clinical trials in the 1990’s to evaluate the impact of β-glucan therapy for controlling infections in high-risk surgical patients.[22] In the initial trial 34 patients were randomly (double-blind, placebo-controlled) assigned to treatment or placebo groups. Patients that received the PGG-glucan had significantly fewer infectious complications than the placebo group (1.4 infections per infected patient for PGG-glucan group vs. 3.4 infections per infected patient for the placebo group). Additional data from the clinical trial revealed that there was decreased use of intravenous antibiotics and shorter stays in the intensive care unit for the patients receiving PGG-glucan vs. patients receiving the placebo. A subsequent human clinical trial [23] further studied the impact of β-glucan for reducing the incidence of infection with high-risk surgical patients. The authors found a similar result with a dose-response trend (higher dose provided greater reduction in infectious occurrences than low doses). In the human clinical trial 67 patients were randomized and received either a placebo or a dose of 0.1, 0.5, 1.0 or 2.0 mg PGG-Glucan per KG of body weight. Serious infections occurred in four patients that received the placebo, three patients that received the low dose (0.1 mg/KG) of PGG-Glucan and only one infection was observed at the highest dose of 2.0 mg/KG of PGG-Glucan. The results of a phase III human clinical trial showed that PGG-Glucan therapy reduced serious post-operative infections by 39% after high-risk noncolorectal operations.[24] This study was conducted in patients that were already as high-risk because of the type of surgery and were more susceptible to infections and other complications. At this point in the development of an injectable form of b-glucan (Betafectin PGG-glucan) most scientists already concluded that yeast-derived b-glucan promoted phagocytosis and subsequent killing of pathogenic bacteria. A phase III clinical trial was proposed and conducted at thirty-nine medical centers in the U.S. involving 1,249 subjects stratified according to colorectal or non-colorectal surgical patients. The PGG-glucan was given once pre-operatively and three times post-operative at 0, 0.5 or 1.0 mg/kg body weight. The measured outcome was serious infection or death of the subjects within 30 days post-surgery. The results of the phase III human clinical trial showed that injectable PGG-Glucan therapy reduced serious post-operative infections by 39% after high-risk noncolorectal operations.[25] There have been studies with humans and animal models that further support the efficacy of β-glucan in combating various infectious diseases. One human study demonstrated that consumption of oral whole glucan particles increased the ability of immune cells to consume a bacterial challenge (phagocytosis). The total number of phagocytic cells and the efficiency of phagocytosis in healthy human study participants increased while consuming a commercial particulate yeast β-glucan. This study demonstrated the potential for yeast β-glucan to increase the reaction rate of the immune system to infectious challenges. The study concluded that oral consumption of whole glucan particles represented a good enhancer of natural immunity. Anthrax is a disease that cannot be tested in human studies for obvious reasons. In a study conducted by the Canadian Department of Defense, Dr. Kournikakis showed that orally administered yeast β-glucan given with or without antibiotics protected mice against anthrax infection.[16] A dose of antibiotics along with oral whole glucan particles (2 mg/KG body weight or 20 mg/KG body weight) for eight days prior to infection with Bacillus anthracis protected mice against anthrax infection over the 10-day post-exposure test period. Mice treated with antibiotic alone did not survive. A second experiment was conducted to investigate the effect of yeast β-glucan orally consumed after exposure of mice to B. anthracis. The results were similar to the previous experiment with an 80-90% survival rate for mice treated with β-glucan, but only 30% for the control group after 10-days of exposure. The hopeful inference is that similar results would be observed with humans. Since there are many commercial products on the market called “glucan”, there is much confusion among consumers as to which type(s) may be the most effective. One of the most comprehensive published studies to date showed Glucan #300, a highly purified yeast glucan, to be “the biologically most relevant immunomodulator” out of a wide ranging group.[26] · Radiation exposure: β-glucan is a well-known biological response modifier (BRM) isolated from the yeast cell wall polysaccharides and is made up entirely of glucose β(1,3)-linked together in linear chains with variable frequency of β(1,6)-linked side chains.[27] Specific hematopoietic activity was first demonstrated with β-glucan in the mid-1980s in an analogous manner as granulocyte monocyte–colony stimulating factor (GM-CSF).[28]Research was carried out initially with particulate β-glucan and later with soluble β-glucans, all of which were administered intravenously to mice.[29][30][31]Mice exposed to 500-900 cGy (500-900 mrads) of gamma radiation exhibited a significantly enhanced recovery of blood leukocyte, platelet and red blood cell counts when given i.v. β-glucan.[32] Other reports showed that β-glucan could reverse the myelo-suppression produced with chemotherapeutic drugs such as fluorouracil,[24] carboplatinum or cyclophosphamide.[33] Moreover, the anti-infective activity of β-glucan combined with its hematopoiesis-stimulating activity resulted in enhanced survival of mice receiving a lethal dose of 900-1200 cGy of radiation.[22] In vitro studies showed that β-glucan could enhance granulocyte and megakaryocyte colony formation by hematopoietic stem progenitor cells when used in combination with GM-CSF and interleukin-3 (IL-3), respectively.[34] Original studies delivered glucan almost entirely by injection. Later, numerous studies tried to evaluate the possibility that glucan can be delivered orally without compromising its biological activities,[12][35][36][37]opening the oral route of administration as a more pleasant alternative. A study by Allendorf et al.[38] clearly demonstrated that oral Beta glucan had hematopoietic effects analogous to Beta glucan administered by i.v. methods, work of Vetvicka’s group showed the mechanisms of the glucan transfer through the gastrointestinal tract.[36] Allendorf et al. demonstrated that orally administered whole glucan particulate functions to accelerate hematopoiesis following irradiation in an analogous manner as i.v. administered β-glucan. Experiments by Cramer et al.[39] or Vetvicka [36] clearly demonstrated that oral β-glucan stimulates hematopoiesis in radiation-treated mice. Currently, there is renewed interest in the potential usefulness of β-glucan as a radioprotective drug for chemotherapy, radiation therapy and nuclear emergencies, particularly because glucan can be used not only as a treatment, but also as a prophylactic. · Septic shock: One of the mechanisms of the immune-enhancing ability of yeast β-glucan is its ability to prime leukocytes to more easily locate and kill non-self cells including bacteria. Early research by Onderdonk et al.[40] investigated the ability of yeast b-glucan to reduce septic infections using in vivo models. Onderdonk et al. found that mice challenged with E. coli or S. aureus bacteria were protected against septic infections when they were injected with PGG-glucan 4–6 hours prior to infection. Additional research further supports that yeast β-glucan reduces septic shock by killing bacteria present in blood. Work by Kernodle et al. demonstrated that preventative dosing of yeast β-glucan prior to infection with S. aureus prevented sepsis in a guinea pig model. [41] Research on the use of yeast β-glucan immunomodulators as a means of treating and preventing bacterial sepsis is well documented.[40][41][42] Recent reports on glucan and sepsis revealed another possible mechanism - glucan protects against oxidative organ injury.[43] · Surgery: There have been numerous studies and clinical trials conducted with the soluble yeast β-glucan particle and the whole glucan particle. Immunomodulators that enhance macrophage function have been shown to be beneficial in human, as well as, animal models. One such study that looked at this correlation examined wound tensile strength and collagen biosynthesis. Positive effects were observed.[44] In a prospective, randomized, double-blind study, 38 trauma patients received an I.V. of a soluble yeast derived glucan for 7 days or placebo. The total mortality rate was significantly less in the glucan group (0% vs. 29%). There was also a decrease in septic morbidity (9.5% vs. 49%). Further such trials to evaluate Biological Response Modifiers (BRM’s) in trauma patients are indicated.[45] Yeast derived beta glucan significantly enhanced phagocytic activity in control and operated mice. In an experimental C. albicans model, mice had induced sepsis along with a midline laparotomy. The non-operated mice on glucan had a 100% survival vs. 73% in the surgical group. Detrimental effects of surgery on survival of C. albicans infection manifested in a 47% survival in the non-surgical vs a 20% survival in the surgery-infected group.[46] The nonspecific immunostimulation of yeast derived glucan appears to have significant potential as a treatment strategy against post-operative infections. In a post splenectomy mouse model, glucan increased survival vs. controls via 75% as opposed to 27%, Severe sepsis enhances risks in both adult and pediatric patients. These works suggest another option beyond prophylactic antibiotics and bacterial vaccines that often have limited success against morbidity and mortality.[47] · Wound healing: Macrophage activity is known to play a key role in wound healing from surgery or trauma. In both animal and human studies, therapy with Beta glucan has provided improvements such as fewer infections, reduced mortality, and stronger tensile strength of scar tissue. · Allergic rhinitis: This disease is caused by an IgE-mediated allergic inflammation of the nasal mucosa. Orally-administered yeast-glucan decreased levels of IL-4 and IL-5 cytokines responsible for the clinical manifestation of this disease, while increased the levels of IL-12. Based on these studies, glucan may have a role as an adjunct to standard treatment in patients with allergic diseases.[48] · Arthritis: Using paramagnetic resonance spectroscopy, yeast-derived glucan was found to cause decline in oxidative tissue damage during the progress of arthritic diseases, suggesting the role in treatment of arthritis.[49] · Additional functions: Influence of certain cereals (barley, oats) and edible mushrooms upon decrease of levels of serum cholesterol and liver low-density lipoproteins, leading to lowering of arteriosclerosis and heart disease hazards, is also mediated by b-glucan.[50] It is known that cereals, mushrooms and yeast facilitate bowel motility and can be used in amelioration of intestinal problems, particularly obstipation.[51][52] Non-digestible b-glucans, forming a remarkable portion of these materials, are also able to modulate mucosal immunity of the intestinal tract.[53] In the central nervous system, β-glucans activate microglial cells.[54] These cells act as scavengers of the brain cell debris and play a positive role in Alzheimer’s disease, AIDS, ischemia injury and multiple sclerosis.[55][56] # Functions in the Body Beta-1,3 glucans improve the body’s immune system defense against foreign invaders by enhancing the ability of macrophages, neutrophils and natural killer cells to respond to and fight a wide range of challenges such as bacteria, viruses, fungi, and parasites. Symptoms and Causes of Deficiency: Beta-1, 3 glucans do not occur naturally in humans, hence no deficiency condition exists. Absorption: For best results, Beta 1, 3-D glucan should be taken on an empty stomach. Enterocytes reportedly facilitate the transportation of beta-1, 3 glucans and similar compounds across the intestinal cell wall into the lymph where they begin to interact with macrophages to activate immune function.[57] Radiolabeled studies have verified that both small and large fragments of beta glucans are found in the serum, which indicates they are absorbed from the intestinal tract.[58] M cells within the Peyer’s Patches physically transport the insoluble whole glucan particles into the GALT.[12] Dietary Sources: Although beta-1 3 glucans occur in baker’s yeast, seaweed, grains such as oats and barley, and numerous mushrooms, they are not readily usable in their natural state. The indigestible cell walls of these substances must be processed in order to free up the beta-1, 3 glucans and make them available for useful purposes. # Yeast Derived Beta Glucan Template:Cleanup-section Yeast Beta 1, 3-D Glucan These are sometimes seen as synonyms: β-Glucan \| (1,3/1,6)-β-D-glucan \| whole glucan particulate \| 1,3/1,6 glucan \| (1→3,1→6) glucan Dosage Range: From 40 mg to 3000 mg daily. Most Common Dosage: Variable, depending upon body weight and whether it is being used for maintenance or an acute condition. As a dietary supplement (maintenance use), the most common dose range has been reported as 40-500 mg per day. When the dosage is reported on a kilogram of body weight basis the dose range is 2-6 mg/kg. If the particulate glucan is being self-administered for an acute condition, a higher dose of 500-3000 mg/day is typically administered. Active Forms: Immune-enhancing activity has been reported for Beta 1, 3-D glucan with 1,6 glucan side chains, which are derived from yeasts. Many varieties of mushrooms have also been reported that have a Beta-1,3/1,4 glucan linkage, similar to glucans from oats and barley. Dosage Forms: As a dietary supplement the most common forms are capsules and tablets. Additional uses also include topical creams and injectables. Toxicities, Cautions, and Contraindications: Beta 1, 3-D glucan has been recognized as GRAS and the FDA has accepted notification of the GRAS affirmation. The specific conditions of manufacture, safety data and product specifications apply only to the Beta 1, 3-D glucan produced by a process as defined in the GRAS dossier and FDA Notification. Although side effects are very rare, occasionally an allergic reaction is reported. All sufficiently purified polysaccharidic immunomodulators distinguish themselves by very low toxicity (e.g., for mouse lentinan has LD50 > 1600 mg/kg). Potential Interactions: Drug/Nutrient Interactions: None known Nutrient/Nutrient Interactions: None known	https://www.wikidoc.org/index.php/Beta-glucan
fd4ee27a8f6964e086c2b5c1177d65096234a053	wikidoc	Beta-lactam	Beta-lactam A beta-lactam ring (β-lactam) or penam is a lactam with a heteroatomic ring structure, consisting of three carbon atoms and one nitrogen atom. The beta-lactam ring is part of the structure of several antibiotic families, principally the penicillins, cephalosporins, carbapenems and monobactams, which are therefore also called beta-lactam antibiotics. These antibiotics work by inhibiting the bacterial cell wall synthesis. This has a lethal effect on bacteria, especially on Gram-positive ones. Bacteria can become resistant against beta-lactam antibiotics by expressing beta-lactamase. # Beta-lactam resistance Because of the popularity of beta-lactam drugs, certain bacteria have been able to develop counter-measures to traditional drug therapies. An enzyme called beta-lactamase is present in many different types of bacteria, which serves to 'break' the beta lactam ring, which effectively nullifies the antibiotic's effectiveness. # Response to beta-lactam resistance As a response to bacterial resistance to beta-lactam drugs, there are drugs, such as Augmentin, which are designed to disable the beta-lactamase enzyme. Augmentin is made of amoxicillin, a beta-lactam antibiotic, and clavulanic acid, a beta-lactamase inhibitor. The clavulanic acid is designed to overwhelm all beta-lactamase enzymes, bind irreversibly to them, and effectively serve as an antagonist so that the amoxicillin is not affected by the beta-lactamase enzymes. # Secondary beta-lactam drug resistance As a response to decreased efficacy of beta-lactamase, some bacteria have changed the proteins that beta-lactam antibiotics bind, the penicillin binding proteins (PBPs). Since the PBPs no longer recognize the beta-lactams, the antibiotics are essentially useless. This is the mechanism behind the methicillin-resistant Staphylococcus aureus (MRSA).	Beta-lactam Template:Wrapper A beta-lactam ring (β-lactam) or penam is a lactam with a heteroatomic ring structure, consisting of three carbon atoms and one nitrogen atom. The beta-lactam ring is part of the structure of several antibiotic families, principally the penicillins, cephalosporins, carbapenems and monobactams, which are therefore also called beta-lactam antibiotics. These antibiotics work by inhibiting the bacterial cell wall synthesis. This has a lethal effect on bacteria, especially on Gram-positive ones. Bacteria can become resistant against beta-lactam antibiotics by expressing beta-lactamase. # Beta-lactam resistance Because of the popularity of beta-lactam drugs, certain bacteria have been able to develop counter-measures to traditional drug therapies. An enzyme called beta-lactamase is present in many different types of bacteria, which serves to 'break' the beta lactam ring, which effectively nullifies the antibiotic's effectiveness. # Response to beta-lactam resistance As a response to bacterial resistance to beta-lactam drugs, there are drugs, such as Augmentin, which are designed to disable the beta-lactamase enzyme. Augmentin is made of amoxicillin, a beta-lactam antibiotic, and clavulanic acid, a beta-lactamase inhibitor. The clavulanic acid is designed to overwhelm all beta-lactamase enzymes, bind irreversibly to them, and effectively serve as an antagonist so that the amoxicillin is not affected by the beta-lactamase enzymes. # Secondary beta-lactam drug resistance As a response to decreased efficacy of beta-lactamase, some bacteria have changed the proteins that beta-lactam antibiotics bind, the penicillin binding proteins (PBPs). Since the PBPs no longer recognize the beta-lactams, the antibiotics are essentially useless. This is the mechanism behind the methicillin-resistant Staphylococcus aureus (MRSA).	https://www.wikidoc.org/index.php/Beta-lactam
6a58468b52e8bbad0b33c826473a7545ea44f669	wikidoc	Bezafibrate	Bezafibrate # Overview Bezafibrate (Bezalip® and various other brand names) is a fibrate drug used for the treatment of hyperlipidaemia. It helps to lower LDL cholesterol and triglyceride in the blood, and increase HDL. # History Bezafibrate was first introduced by Boehringer Mannheim in 1977. # Use Adjunct to diet and other therapeutic measures for treatment of type IIa and IIb mixed [[hyperlipidemia, to regulate lipid and apoprotein levels; treatment of adult patients with high to very high triglyceride levels (Fredrickson classification type IV and V hyperlipidemias), who are at high risk of sequelae and complications from their dyslipidemia. Bezafibrate improves markers of combined hyperlipidemia, effectively reducing LDL and triglycerides and improving HDL levels. The main effect on cardiovascular morbidity is in patients with the metabolic syndrome, the features of which are attenuated by bezafibrate. Studies show that in patients with impaired glucose tolerance, bezafibrate may delay progress to diabetes, and in those with insulin resistance it slowed progress in the HOMA severity marker. # Administration Immediate release: Do not crush or chew; tablet should be swallowed whole and with sufficient fluid, with or after meals Sustained release: Do not crush or chew; tablet should be swallowed whole with sufficient fluid. Take in morning or evening with or after meals # Pregnancy Risk Factor Not available; not recommended (per manufacturer) # Pregnancy Implications Embryotoxicity has occurred in animals at toxic doses. Women planning pregnancy should discontinue bezafibrate several months before conception; strict birth control procedures must be exercised. # Lactation Excretion in breast milk unknown/contraindicated # Contraindications Hypersensitivity to bezafibrate, fibrates, or any component of the formulation; hepatic or renal dysfunction; primary biliary cirrhosis; preexisting gallbladder disease; concurrent use of MAO inhibitors; pregnancy or breast-feeding; not indicated for the treatment of type I hyperlipoproteinemia # Warnings/Precautions Has been shown to be hepatotoxic and possibly tumorigenic (animal models); discontinue if response is not obtained in 3 months. Use caution in patients with history of jaundice or hepatic disorder; abnormal liver function tests have been observed (reversible when discontinued). Bezafibrate has been associated with rare myositis or rhabdomyolysis; risk may be increased by concurrent therapy with HMG CoA reductase inhibitors or cyclosporine. Use caution in renal impairment (dosage reduction required). Use with caution in patients with hypoalbuminemia or nephrotic syndrome. Limited experience is available in children; therefore, caution should be used when treating children. # Adverse Reactions 1% to 10% Central nervous system: Dizziness (2%), insomnia (1%), migraine (1%), pain (1%) Dermatologic: Pruritus (3%), eczema (1%), rash Gastrointestinal: Gastritis (6%), flatulence (5%), dyspepsia (3%), nausea, diarrhea, constipation Hematologic: Anemia (1%) Hepatic: Transaminases increased Miscellaneous: Allergic reaction (1%) Neuromuscular and skeletal: CPK increased Renal: Creatinine increased <1%: Alkaline phosphatase increased, alopecia, asthenia, cholelithiasis, epigastric distress, erythema, headache, impotence, muscle pain, muscle cramps, myopathy, rhabdomyolysis, urticaria # Overdosage/Toxicology Limited information. Symptomatic and supportive measures should be taken; hemodialysis should not be considered. In patients with existing renal dysfunction (if dosage recommendations are not followed), over dosage may occur and severe rhabdomyolysis may develop. # Drug Interactions - Substrate of CYP3A4 (minor) - Cholestyramine and colestipol: May impair bezafibrate absorption (separate doses by at least 2 hours). - Cyclosporine: Severe myositis and rhabdomyolysis have been reported with concurrent use. - Furosemide: Blood levels of furosemide and fibric acid derivatives (i.e., clofibrate and fenofibrate) may be increased during concurrent dosing (particularly in hypoalbuminemia). Limited documentation; monitor for increased effect/toxicity. - HMG-CoA reductase inhibitors: Severe myositis and rhabdomyolysis have been reported with concurrent use; use extreme caution. - MAO inhibitors: May increase the risk of hepatotoxicity. - Warfarin (oral anticoagulants): May increase prothrombin time; dosage of oral anticoagulant should be reduced by 50%. # Stability Store at room temperature of 15°C to 30°C (59°F to 86°F); protect from high humidity. # Mechanism of Action Mechanism not definitely established; may increase VLDL catabolism by increasing lipoprotein and hepatic triglyceride lipase activities; attenuation of triglyceride biosynthesis by inhibition of acetyl-CoA carboxylase; decreased cholesterol biosynthesis by inhibition of 3-hydroxy-3-methyglutaryl-coenzyme A reductase # Pharmacodynamics/Kinetics Absorption: Immediate release: Almost completely; Sustained release: 70% Distribution: 17 L Protein binding: 94% to 96% Half-life elimination: 1-2 hours Time to peak, serum: Immediate release: 1-2 hours; Sustained release: 3-4 hours Excretion: Urine (95%); feces (3%) Like the other fibrates, bezafibrate is an agonist of PPARα; some studies suggest it may have some activity on PPARγ and PPARδ as well. # Dosage Oral: Adults: Immediate release: 200 mg 2-3 times/day; may reduce to 200 mg twice daily in patients with good response Sustained release: 400 mg once daily Dosing interval in renal impairment: Clcr >60 mL/minute: 200 mg 3 times/day Clcr 60-40 mL/minute: 200 mg 2 times/day Clcr 40-15 mL/minute: 200 mg every 1-2 days Clcr<15 mL/minute: 200 mg every 3 days Hemodialysis: 200 mg every 3 days # Monitoring Parameters Periodic evaluation of serum lipids, cholesterol, and triglycerides (especially in the first few months of therapy). LFTs after 3-6 months; then annually. CBC (periodically during the first 12 months). Fasting glucose, creatinine, and CPK periodically. # Test Interactions Glucose, creatinine, ALT, CGT, and CPK # Dietary Considerations Should be taken with or after meals. Before initiation of therapy, patients should be placed on a standard lipid-lowering diet for 6 weeks and the diet should be continued during drug therapy. # Patient Education Comply exactly to the terms of the prescription; do not change the dose or stop prescription without your prescriber's advice. Medication is meant to supplement an appropriate diet. Inform prescriber if you suffer from liver or kidney disease or are taking other medications (especially warfarin or cyclosporine). Swallow tablets without chewing and with sufficient fluid, with or after meals. If you are also taking cholestyramine or a bile acid resin, separate doses by at least 2 hours. Call prescriber if you experience abdominal pain, constipation, diarrhea, nausea, headache, dizziness, skin reactions, muscular pain or cramps, and fatigue. You will need regular check-ups and laboratory monitoring as recommended by your prescriber. Pregnancy / breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed. # Nursing Implications Monitor serum lipids, LFTs, CBC # Dental Health: Effects on Dental Treatment No significant effects or complications reported Dental Health: Vasoconstrictor/Local Anesthetic Precautions No information available to require special precautions # Mental Health: Effects on Mental Status May cause dizziness or insomnia Mental Health: Effects on Psychiatric Treatment Contraindicated with MAO inhibitors # Available Dosage Forms Tablet, immediate release: 200 mg Tablet, sustained release: 400 mg # Side-effects The main toxicity is hepatic (abnormal liver enzymes), and myopathy and rarely rhabdomyolysis have been reported. # Other uses The Australian biotech company Giaconda combines bezafibrate with chenodeoxycholic acid in an anti-hepatitis C drug combination called Hepaconda. # International Brand Names Azufibrat® (DE); Befibrat® (DE); Béfizal® (FR); Beza 1A Pharma® (DE); Beza AbZ® (DE); Bezabeta® (DE); Bezacur® (AR, DE, LU); Bezacur® Retard (CL); Bezadoc® (DE); Bezafibrat 1A Pharma® (AT); Bezafibrat AL® (DE); Bezafibrat Arcana® (AT); Bezafibrate® (GB, ID, IL); Bezafibrat Genericon® (AT); Bezafibrat Heumann® (DE); Bezafibrat Lannacher® (AT); Bezafibrato Genfar® (EC); Bezafibrat PB® (DE); Bezafibrat Ratiopharm® (AT); Bezafibrat-ratiopharm® (DE); Bezafibrat Sandoz® (DE); Bezafibrat Stada® (DE); Bezafibrat Stada Retard® (SG); bezafibrat von ct® (DE); Bezafisal® (MX); Bezagamma® (DE); Bezagen® (GB); Bezalip® (AT, BE, BR, CA, CH, CO, CR, CZ, DE, DO, EC, ES, FI, FR, GB, GT, HK, HU, ID, IN, IT, JO, JP, LU, MX, NL, NZ, PA, PH, SE, SG, SV, TH, TW, ZA); Bezalip® Retard (AT, IL, PL, RO, SE, SG, TH); Bezamerck® (DE); Bezamidin® (PL); Bezamil® (TH); Bezapharm® (DE); Bezastad® (AT); Bezatol® (JP); Cedur® (BE, BR, CH, DE, LU); Cholestenorm® (RU); Decolest® (RO); Difaterol® (ES); Elpi Lip® (AR); Eulitop® (BE, ES); Fibalip® (NZ); Hadiel® (IT); Lacromid® (CY); Liparol® (GB); Lipox® (DE); Nebufurd Retard® (AR); Nimus® (CL); Norlip® (IL); Oralipin® (CL); Oralipin Retard® (CL); PMS-Bezafibrate (CA); Polyzalip® (TH); Raset® (TH); Reducterol® (ES); Regadrin B® (CZ, DE, RO); Rolab-Bezafibrate® (ZA); Sklerofibrat® (DE); Solibay® (MX); Verbital® (RO); Zafibral® (SG); Zimbacol® (GB)	Bezafibrate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] # For patient information, click here # Overview Bezafibrate (Bezalip® and various other brand names) is a fibrate drug used for the treatment of hyperlipidaemia. It helps to lower LDL cholesterol and triglyceride in the blood, and increase HDL. # History Bezafibrate was first introduced by Boehringer Mannheim in 1977. # Use Adjunct to diet and other therapeutic measures for treatment of type IIa and IIb mixed [[hyperlipidemia, to regulate lipid and apoprotein levels; treatment of adult patients with high to very high triglyceride levels (Fredrickson classification type IV and V hyperlipidemias), who are at high risk of sequelae and complications from their dyslipidemia. Bezafibrate improves markers of combined hyperlipidemia, effectively reducing LDL and triglycerides and improving HDL levels.[1] The main effect on cardiovascular morbidity is in patients with the metabolic syndrome, the features of which are attenuated by bezafibrate.[2] Studies show that in patients with impaired glucose tolerance, bezafibrate may delay progress to diabetes[3], and in those with insulin resistance it slowed progress in the HOMA severity marker.[4] # Administration Immediate release: Do not crush or chew; tablet should be swallowed whole and with sufficient fluid, with or after meals Sustained release: Do not crush or chew; tablet should be swallowed whole with sufficient fluid. Take in morning or evening with or after meals # Pregnancy Risk Factor Not available; not recommended (per manufacturer) # Pregnancy Implications Embryotoxicity has occurred in animals at toxic doses. Women planning pregnancy should discontinue bezafibrate several months before conception; strict birth control procedures must be exercised. # Lactation Excretion in breast milk unknown/contraindicated # Contraindications Hypersensitivity to bezafibrate, fibrates, or any component of the formulation; hepatic or renal dysfunction; primary biliary cirrhosis; preexisting gallbladder disease; concurrent use of MAO inhibitors; pregnancy or breast-feeding; not indicated for the treatment of type I hyperlipoproteinemia # Warnings/Precautions Has been shown to be hepatotoxic and possibly tumorigenic (animal models); discontinue if response is not obtained in 3 months. Use caution in patients with history of jaundice or hepatic disorder; abnormal liver function tests have been observed (reversible when discontinued). Bezafibrate has been associated with rare myositis or rhabdomyolysis; risk may be increased by concurrent therapy with HMG CoA reductase inhibitors or cyclosporine. Use caution in renal impairment (dosage reduction required). Use with caution in patients with hypoalbuminemia or nephrotic syndrome. Limited experience is available in children; therefore, caution should be used when treating children. # Adverse Reactions 1% to 10% Central nervous system: Dizziness (2%), insomnia (1%), migraine (1%), pain (1%) Dermatologic: Pruritus (3%), eczema (1%), rash Gastrointestinal: Gastritis (6%), flatulence (5%), dyspepsia (3%), nausea, diarrhea, constipation Hematologic: Anemia (1%) Hepatic: Transaminases increased Miscellaneous: Allergic reaction (1%) Neuromuscular and skeletal: CPK increased Renal: Creatinine increased <1%: Alkaline phosphatase increased, alopecia, asthenia, cholelithiasis, epigastric distress, erythema, headache, impotence, muscle pain, muscle cramps, myopathy, rhabdomyolysis, urticaria # Overdosage/Toxicology Limited information. Symptomatic and supportive measures should be taken; hemodialysis should not be considered. In patients with existing renal dysfunction (if dosage recommendations are not followed), over dosage may occur and severe rhabdomyolysis may develop. # Drug Interactions - Substrate of CYP3A4 (minor) - Cholestyramine and colestipol: May impair bezafibrate absorption (separate doses by at least 2 hours). - Cyclosporine: Severe myositis and rhabdomyolysis have been reported with concurrent use. - Furosemide: Blood levels of furosemide and fibric acid derivatives (i.e., clofibrate and fenofibrate) may be increased during concurrent dosing (particularly in hypoalbuminemia). Limited documentation; monitor for increased effect/toxicity. - HMG-CoA reductase inhibitors: Severe myositis and rhabdomyolysis have been reported with concurrent use; use extreme caution. - MAO inhibitors: May increase the risk of hepatotoxicity. - Warfarin (oral anticoagulants): May increase prothrombin time; dosage of oral anticoagulant should be reduced by 50%. # Stability Store at room temperature of 15°C to 30°C (59°F to 86°F); protect from high humidity. # Mechanism of Action Mechanism not definitely established; may increase VLDL catabolism by increasing lipoprotein and hepatic triglyceride lipase activities; attenuation of triglyceride biosynthesis by inhibition of acetyl-CoA carboxylase; decreased cholesterol biosynthesis by inhibition of 3-hydroxy-3-methyglutaryl-coenzyme A reductase # Pharmacodynamics/Kinetics Absorption: Immediate release: Almost completely; Sustained release: 70% Distribution: 17 L Protein binding: 94% to 96% Half-life elimination: 1-2 hours Time to peak, serum: Immediate release: 1-2 hours; Sustained release: 3-4 hours Excretion: Urine (95%); feces (3%) Like the other fibrates, bezafibrate is an agonist of PPARα; some studies suggest it may have some activity on PPARγ and PPARδ as well. # Dosage Oral: Adults: Immediate release: 200 mg 2-3 times/day; may reduce to 200 mg twice daily in patients with good response Sustained release: 400 mg once daily Dosing interval in renal impairment: Clcr >60 mL/minute: 200 mg 3 times/day Clcr 60-40 mL/minute: 200 mg 2 times/day Clcr 40-15 mL/minute: 200 mg every 1-2 days Clcr<15 mL/minute: 200 mg every 3 days Hemodialysis: 200 mg every 3 days # Monitoring Parameters Periodic evaluation of serum lipids, cholesterol, and triglycerides (especially in the first few months of therapy). LFTs after 3-6 months; then annually. CBC (periodically during the first 12 months). Fasting glucose, creatinine, and CPK periodically. # Test Interactions Glucose, creatinine, ALT, CGT, and CPK # Dietary Considerations Should be taken with or after meals. Before initiation of therapy, patients should be placed on a standard lipid-lowering diet for 6 weeks and the diet should be continued during drug therapy. # Patient Education Comply exactly to the terms of the prescription; do not change the dose or stop prescription without your prescriber's advice. Medication is meant to supplement an appropriate diet. Inform prescriber if you suffer from liver or kidney disease or are taking other medications (especially warfarin or cyclosporine). Swallow tablets without chewing and with sufficient fluid, with or after meals. If you are also taking cholestyramine or a bile acid resin, separate doses by at least 2 hours. Call prescriber if you experience abdominal pain, constipation, diarrhea, nausea, headache, dizziness, skin reactions, muscular pain or cramps, and fatigue. You will need regular check-ups and laboratory monitoring as recommended by your prescriber. Pregnancy / breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed. # Nursing Implications Monitor serum lipids, LFTs, CBC # Dental Health: Effects on Dental Treatment No significant effects or complications reported Dental Health: Vasoconstrictor/Local Anesthetic Precautions No information available to require special precautions # Mental Health: Effects on Mental Status May cause dizziness or insomnia Mental Health: Effects on Psychiatric Treatment Contraindicated with MAO inhibitors # Available Dosage Forms Tablet, immediate release: 200 mg Tablet, sustained release: 400 mg # Side-effects The main toxicity is hepatic (abnormal liver enzymes), and myopathy and rarely rhabdomyolysis have been reported. # Other uses The Australian biotech company Giaconda combines bezafibrate with chenodeoxycholic acid in an anti-hepatitis C drug combination called Hepaconda. # International Brand Names Azufibrat® (DE); Befibrat® (DE); Béfizal® (FR); Beza 1A Pharma® (DE); Beza AbZ® (DE); Bezabeta® (DE); Bezacur® (AR, DE, LU); Bezacur® Retard (CL); Bezadoc® (DE); Bezafibrat 1A Pharma® (AT); Bezafibrat AL® (DE); Bezafibrat Arcana® (AT); Bezafibrate® (GB, ID, IL); Bezafibrat Genericon® (AT); Bezafibrat Heumann® (DE); Bezafibrat Lannacher® (AT); Bezafibrato Genfar® (EC); Bezafibrat PB® (DE); Bezafibrat Ratiopharm® (AT); Bezafibrat-ratiopharm® (DE); Bezafibrat Sandoz® (DE); Bezafibrat Stada® (DE); Bezafibrat Stada Retard® (SG); bezafibrat von ct® (DE); Bezafisal® (MX); Bezagamma® (DE); Bezagen® (GB); Bezalip® (AT, BE, BR, CA, CH, CO, CR, CZ, DE, DO, EC, ES, FI, FR, GB, GT, HK, HU, ID, IN, IT, JO, JP, LU, MX, NL, NZ, PA, PH, SE, SG, SV, TH, TW, ZA); Bezalip® Retard (AT, IL, PL, RO, SE, SG, TH); Bezamerck® (DE); Bezamidin® (PL); Bezamil® (TH); Bezapharm® (DE); Bezastad® (AT); Bezatol® (JP); Cedur® (BE, BR, CH, DE, LU); Cholestenorm® (RU); Decolest® (RO); Difaterol® (ES); Elpi Lip® (AR); Eulitop® (BE, ES); Fibalip® (NZ); Hadiel® (IT); Lacromid® (CY); Liparol® (GB); Lipox® (DE); Nebufurd Retard® (AR); Nimus® (CL); Norlip® (IL); Oralipin® (CL); Oralipin Retard® (CL); PMS-Bezafibrate (CA); Polyzalip® (TH); Raset® (TH); Reducterol® (ES); Regadrin B® (CZ, DE, RO); Rolab-Bezafibrate® (ZA); Sklerofibrat® (DE); Solibay® (MX); Verbital® (RO); Zafibral® (SG); Zimbacol® (GB)	https://www.wikidoc.org/index.php/Bezafibrate
f8381cbc322eb0bfc88c849595b13bb82c7151f8	wikidoc	Bezitramide	Bezitramide # Overview Bezitramide is an opioid analgesic. Bezitramide itself is a prodrug which is readily hydrolyzed in the gastrointestinal tract to its main metabolite, despropionyl-bezitramide. Bezitramide was discovered at Janssen Pharmaceutica in 1961. It is most commonly marketed under the trade name Burgodin. The drug was pulled from the shelves in the Netherlands in 2004 after fatal overdose cases, including one where a five-year-old child took one tablet from his mother's purse, ate it, and promptly died. Bezitramide is regulated much the same as morphine in all known jurisdictions and is a Schedule II substance under the United States' Controlled Substances Act of 1970, with an ACSCN of 9800 and zero annual manufacturing quota. However, it has to this point never been marketed in the United States.	Bezitramide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Bezitramide is an opioid analgesic. Bezitramide itself is a prodrug which is readily hydrolyzed in the gastrointestinal tract to its main metabolite, despropionyl-bezitramide. Bezitramide was discovered at Janssen Pharmaceutica in 1961. It is most commonly marketed under the trade name Burgodin. The drug was pulled from the shelves in the Netherlands in 2004 after fatal overdose cases, including one where a five-year-old child took one tablet from his mother's purse, ate it, and promptly died. Bezitramide is regulated much the same as morphine in all known jurisdictions and is a Schedule II substance under the United States' Controlled Substances Act of 1970, with an ACSCN of 9800 and zero annual manufacturing quota. However, it has to this point never been marketed in the United States.	https://www.wikidoc.org/index.php/Bezitramide
5a651873c149a5258b543a9e63fd4f7a70570ed6	wikidoc	Bibliomania	Bibliomania # Overview Bibliomania is an obsessive-compulsive disorder involving the collecting or hoarding of books to the point where social relations or health are damaged. One of several psychological disorders associated with books, bibliomania is characterized by the collecting of books which have no use to the collector nor any great intrinsic value to a genuine book collector. The purchase of multiple copies of the same book and edition and the accumulation of books beyond possible capacity of use or enjoyment are frequent symptoms of bibliomania. Bibliomania is not to be confused with bibliophily, which is the usual love of books and is not considered a clinical psychological disorder. Other abnormal behaviours involving books include book-eating (bibliophagy), compulsive book-stealing (bibliokleptomania), book-burying (bibliotaphy), bibliocaust, etc. # Examples ## People with bibliomania - Stephen Blumberg - Thomas Phillipps (1792-1872) suffered from severe bibliomania. His collection, which at his death contained over 160,000 books and manuscripts, was still being auctioned off over 100 years after his death. - Rev. W.F. Whitcher 18th century Methodist pastor who after having stolen and rebound rare books, would assert they were rare "finds" from local booksellers. ## Fictional characters with bibliomania - Mel Gibson's character in the movie Conspiracy Theory suffers from triggered bibliomania, a form of mind-control that prompts him to buy a copy of J.D. Salinger's Catcher In The Rye every time he goes outside his apartment. (cf. MK-ULTRA papers, National Security Archives.) - Yomiko Readman codename "The Paper" is a character in the anime Read or Die. She is a "paper user" who works for the British Library. She is also a bibliomane, whose apartment is literally stacked floor to ceiling with books. It is stated at one point in R.O.D the TV that she has read "thousands of books in her lifetime" which makes her unusual among bibliomanes, as most collect books because of a psychological problem, and do not actually read any of them. # Further reading - Jackson, Holbrook (2001). The Anatomy of Bibliomania. Urbana: University of Illinois Press. ISBN 0252070437..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} - Dibdin, Thomas Frognall (1811). Bibliomania: Or Book Madness. - Basbanes, Nicholas A. (1995). A Gentle Madness: Bibliophiles, Bibliomanes, and the Eternal Passion for Books. Henry Holt and Company, Inc.	Bibliomania Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Bibliomania is an obsessive-compulsive disorder involving the collecting or hoarding of books to the point where social relations or health are damaged. One of several psychological disorders associated with books, bibliomania is characterized by the collecting of books which have no use to the collector nor any great intrinsic value to a genuine book collector. The purchase of multiple copies of the same book and edition and the accumulation of books beyond possible capacity of use or enjoyment are frequent symptoms of bibliomania. Bibliomania is not to be confused with bibliophily, which is the usual love of books and is not considered a clinical psychological disorder. Other abnormal behaviours involving books include book-eating (bibliophagy), compulsive book-stealing (bibliokleptomania), book-burying (bibliotaphy), bibliocaust, etc. # Examples ## People with bibliomania - Stephen Blumberg - Thomas Phillipps[1] (1792-1872) suffered from severe bibliomania. His collection, which at his death contained over 160,000 books and manuscripts, was still being auctioned off over 100 years after his death. - Rev. W.F. Whitcher[2] 18th century Methodist pastor who after having stolen and rebound rare books, would assert they were rare "finds" from local booksellers. ## Fictional characters with bibliomania - Mel Gibson's character in the movie Conspiracy Theory suffers from triggered bibliomania, a form of mind-control that prompts him to buy a copy of J.D. Salinger's Catcher In The Rye every time he goes outside his apartment. (cf. MK-ULTRA papers, National Security Archives.) - Yomiko Readman codename "The Paper" is a character in the anime Read or Die. She is a "paper user" who works for the British Library. She is also a bibliomane, whose apartment is literally stacked floor to ceiling with books. It is stated at one point in R.O.D the TV that she has read "thousands of books in her lifetime" which makes her unusual among bibliomanes, as most collect books because of a psychological problem, and do not actually read any of them. # Further reading - Jackson, Holbrook (2001). The Anatomy of Bibliomania. Urbana: University of Illinois Press. ISBN 0252070437..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} - Dibdin, Thomas Frognall (1811). Bibliomania: Or Book Madness. - Basbanes, Nicholas A. (1995). A Gentle Madness: Bibliophiles, Bibliomanes, and the Eternal Passion for Books. Henry Holt and Company, Inc.	https://www.wikidoc.org/index.php/Bibliomania
ccd88448cb4719bc4d922e9c4b9f6b0b4e6b19a2	wikidoc	Bicarbonate	Bicarbonate # Overview In inorganic chemistry, a bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. # Chemical properties The bicarbonate ion (hydrogen carbonate) is an anion with the empirical formula HCO3− and a molecular mass of 61.01 daltons; it consists of one central carbon atom surrounded by three oxygen atoms in a trigonal planar arrangement, with a hydrogen atom attached to one of the oxygens. The bicarbonate ion carries a negative one formal charge and is the conjugate base of carbonic acid, H2CO3; it is the conjugate acid of CO32−, the carbonate ion as shown by these equilibrium reactions. CO32- +2 H2O ⇋ HCO31- + H2O + OH1- ⇋ H2CO3 +2 OH1- H2CO3 +2 H2O ⇋ HCO31- + H3O1+ + H2O ⇋ CO32- +2 H3O1+ A bicarbonate salt forms when a positively charged ion attaches to the negatively charged oxygen atoms of the ion, forming an ionic compound. Many bicarbonates are soluble in water at standard temperature and pressure, particularly sodium bicarbonate and magnesium bicarbonate; both of these substances contribute to total dissolved solids, a common parameter for assessing water quality. # Physiological role Bicarbonate is a crucial component of the pH buffering system of the body (maintaining homeostasis). 86%-90% of CO2 in the body is converted into carbonic acid (H2CO3), which can quickly turn into bicarbonate (HCO3-). With carbonic acid as the central intermediate species, bicarbonate, in conjunction with water, hydrogen ions, and carbon dioxide forms this buffering system which is maintained at the volatile equilibrium required to provide prompt resistance to drastic pH changes in both the acidic and basic directions. This is especially important for protecting tissues of the central nervous system, where pH changes too far outside of the normal range in either direction could prove disastrous. (See acidosis, or alkalosis.) # Other uses The most common salt of the bicarbonate ion is sodium bicarbonate, NaHCO3, which is used as baking soda. When exposed to an acid such as acetic acid (vinegar), bicarbonates release carbon dioxide. This is used as a leavening agent in baking. The flow of bicarbonate ions from rocks weathered by the carbonic acid in rainwater is an important part of the carbon cycle. Bicarbonate also serves in the digestive system. It raises the internal pH of the stomach, after highly acidic digestive juices have finished in their digestion of food. # Bicarbonate Compounds - Sodium bicarbonate - Potassium bicarbonate - Calcium bicarbonate - Ammonium bicarbonate - Carbonic anhydrase	Bicarbonate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In inorganic chemistry, a bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. # Chemical properties The bicarbonate ion (hydrogen carbonate) is an anion with the empirical formula HCO3− and a molecular mass of 61.01 daltons; it consists of one central carbon atom surrounded by three oxygen atoms in a trigonal planar arrangement, with a hydrogen atom attached to one of the oxygens. The bicarbonate ion carries a negative one formal charge and is the conjugate base of carbonic acid, H2CO3; it is the conjugate acid of CO32−, the carbonate ion as shown by these equilibrium reactions. CO32- +2 H2O ⇋ HCO31- + H2O + OH1- ⇋ H2CO3 +2 OH1- H2CO3 +2 H2O ⇋ HCO31- + H3O1+ + H2O ⇋ CO32- +2 H3O1+ A bicarbonate salt forms when a positively charged ion attaches to the negatively charged oxygen atoms of the ion, forming an ionic compound. Many bicarbonates are soluble in water at standard temperature and pressure, particularly sodium bicarbonate and magnesium bicarbonate; both of these substances contribute to total dissolved solids, a common parameter for assessing water quality. # Physiological role Bicarbonate is a crucial component of the pH buffering system of the body (maintaining homeostasis). 86%-90% of CO2 in the body is converted into carbonic acid (H2CO3), which can quickly turn into bicarbonate (HCO3-). With carbonic acid as the central intermediate species, bicarbonate, in conjunction with water, hydrogen ions, and carbon dioxide forms this buffering system which is maintained at the volatile equilibrium required to provide prompt resistance to drastic pH changes in both the acidic and basic directions. This is especially important for protecting tissues of the central nervous system, where pH changes too far outside of the normal range in either direction could prove disastrous. (See acidosis, or alkalosis.) # Other uses The most common salt of the bicarbonate ion is sodium bicarbonate, NaHCO3, which is used as baking soda. When exposed to an acid such as acetic acid (vinegar), bicarbonates release carbon dioxide. This is used as a leavening agent in baking. The flow of bicarbonate ions from rocks weathered by the carbonic acid in rainwater is an important part of the carbon cycle. Bicarbonate also serves in the digestive system. It raises the internal pH of the stomach, after highly acidic digestive juices have finished in their digestion of food. # Bicarbonate Compounds - Sodium bicarbonate - Potassium bicarbonate - Calcium bicarbonate - Ammonium bicarbonate - Carbonic anhydrase	https://www.wikidoc.org/index.php/Bicarbonate
bf7babafbabc3542e64bb750ffc5c2a402f49653	wikidoc	Big Tobacco	Big Tobacco Big Tobacco is a pejorative term often applied to the tobacco industry in general, or more particularly to the "big three" tobacco corporations in the United States. The phrase is often used in TheTruth.com, the Campaign for Tobacco-Free Kids, and other anti-smoking ad campaigns funded by the Master Settlement Agreement. The term usually refers to tobacco companies Philip Morris (Altria),R. J. Reynolds (RJR) and British American Tobacco, but can also include other companies with a major stake in tobacco consumption, such as Lorillard or Brown & Williamson. # Other uses One of the villains in the comic movie Mystery Men, the cigar-chomping leader of a business-themed gang, uses the pseudonym 'Big Tobacco'. In addition, Big Tobacco is featured in the movie Thank You for Smoking. Nick Naylor (Aaron Eckhart) plays a lobbyist for Big Tobacco. "Big Tobacco didn't spend billions of dollars making it impossible to quit smoking so that anyone with a hammer, an ice pick, and good aim could make it any easier." Stephen Colbert	Big Tobacco Big Tobacco is a pejorative term often applied to the tobacco industry in general, or more particularly to the "big three" tobacco corporations in the United States. The phrase is often used in TheTruth.com, the Campaign for Tobacco-Free Kids, and other anti-smoking ad campaigns funded by the Master Settlement Agreement. The term usually refers to tobacco companies Philip Morris (Altria),R. J. Reynolds (RJR) and British American Tobacco, but can also include other companies with a major stake in tobacco consumption, such as Lorillard or Brown & Williamson. # Other uses One of the villains in the comic movie Mystery Men, the cigar-chomping leader of a business-themed gang, uses the pseudonym 'Big Tobacco'. In addition, Big Tobacco is featured in the movie Thank You for Smoking. Nick Naylor (Aaron Eckhart) plays a lobbyist for Big Tobacco. "Big Tobacco didn't spend billions of dollars making it impossible to quit smoking so that anyone with a hammer, an ice pick, and good aim could make it any easier." Stephen Colbert	https://www.wikidoc.org/index.php/Big_Tobacco
f6ac26a1ffa5cd97d500b0ac79171bf46b500c69	wikidoc	Bimatoprost	Bimatoprost # 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 Bimatoprost is a prostaglandin analog that is FDA approved for the {{{indicationType}}} of open angle glaucoma or ocular hypertension. Common adverse reactions include conjunctival hyperemia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - LUMIGAN® (bimatoprost ophthalmic solution) 0.01% is indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension. - The recommended dosage is one drop in the affected eye(s) once daily in the evening. LUMIGAN® (bimatoprost ophthalmic solution) 0.01% should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect. - Reduction of the intraocular pressure starts approximately 4 hours after the first administration with maximum effect reached within approximately 8 to 12 hours. - LUMIGAN® 0.01% may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bimatoprost in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bimatoprost in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Bimatoprost in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bimatoprost in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bimatoprost in pediatric patients. # Contraindications - None # Warnings ### Precautions - Pigmentation - Bimatoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as bimatoprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of bimatoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known. - Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with LUMIGAN® (bimatoprost ophthalmic solution) 0.01% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. - Eyelash Changes - LUMIGAN® 0.01% may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment. - Intraocular Inflammation - Prostaglandin analogs, including bimatoprost, have been reported to cause intraocular inflammation. In addition, because these products may exacerbate inflammation, caution should be used in patients with active intraocular inflammation (e.g., uveitis). - Macular Edema - Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic solution. LUMIGAN® 0.01% should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. - Bacterial Keratitis - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. - Use with Contact Lenses - Contact lenses should be removed prior to instillation of LUMIGAN® 0.01% and may be reinserted 15 minutes following its administration. # 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. - In a 12-month clinical study with bimatoprost ophthalmic solutions 0.01%, the most common adverse reaction was conjunctival hyperemia (31%). Approximately 1.6% of patients discontinued therapy due to conjunctival hyperemia. Other adverse drug reactions (reported in 1 to 4% of patients) with LUMIGAN® 0.01% in this study included conjunctival edema, conjunctival hemorrhage, eye irritation, eye pain, eye pruritus, erythema of eyelid, eyelids pruritus, growth of eyelashes, hypertrichosis, instillation site irritation, punctate keratitis, skin hyperpigmentation, vision blurred, and visual acuity reduced. ## Postmarketing Experience - The following reaction has been identified during postmarketing use of LUMIGAN® 0.01% in clinical practice. Because it was reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reaction, which has been chosen for inclusion due to either its seriousness, frequency of reporting, possible causal connection to LUMIGAN® 0.01%, or a combination of these factors, includes headache. - In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed. # Drug Interactions There is limited information regarding Bimatoprost Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of bimatoprost which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood AUC levels. - At doses at least 41 times the maximum intended human exposure based on blood AUC levels, the gestation length was reduced in the dams, the incidence of dead fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup body weights were reduced. - There are no adequate and well-controlled studies of LUMIGAN® (bimatoprost ophthalmic solution) 0.01% administration in pregnant women. Because animal reproductive studies are not always predictive of human response LUMIGAN® 0.01% should be administered 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 Bimatoprost in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bimatoprost during labor and delivery. ### Nursing Mothers - It is not known whether LUMIGAN® 0.01% is excreted in human milk, although in animal studies, bimatoprost has been shown to be excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when LUMIGAN® 0.01% is administered to a nursing woman. ### Pediatric Use - Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use. ### Geriatic Use - No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients. ### Gender There is no FDA guidance on the use of Bimatoprost with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bimatoprost with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bimatoprost in patients with renal impairment. ### Hepatic Impairment - In patients with a history of liver disease or abnormal ALT, AST and/or bilirubin at baseline, bimatoprost 0.03% had no adverse effect on liver function over 48 months. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bimatoprost in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bimatoprost in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Bimatoprost in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Bimatoprost in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - No information is available on overdosage in humans. In oral (by gavage) mouse and rat studies, doses up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 210 times higher than the accidental dose of one bottle of LUMIGAN® 0.01% for a 10 kg child. ### Management - If overdose with LUMIGAN® (bimatoprost ophthalmic solution) 0.01% occurs, treatment should be symptomatic. ## Chronic Overdose There is limited information regarding Chronic Overdose of Bimatoprost in the drug label. # Pharmacology ## Mechanism of Action - Bimatoprost, a prostaglandin analog, is a synthetic structural analog of prostaglandin with ocular hypotensive activity. It selectively mimics the effects of naturally occurring substances, prostamides. Bimatoprost is believed to lower intraocular pressure (IOP) in humans by increasing outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Elevated IOP presents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. ## Structure - LUMIGAN® (bimatoprost ophthalmic solution) 0.01% is a synthetic prostamide analog with ocular hypotensive activity. Its chemical name is (Z)-7-cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular formula is C25H37NO4. Its chemical structure is: - Bimatoprost is a powder, which is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. LUMIGAN® 0.01% is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg. - LUMIGAN® 0.01% contains Active: bimatoprost 0.1 mg/mL; Inactives: benzalkonium chloride 0.2 mg/mL; sodium chloride; sodium phosphate, dibasic; citric acid; and purified water. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8-7.8. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Bimatoprost in the drug label. ## Pharmacokinetics - Absorption: After one drop of bimatoprost ophthalmic solution 0.03% was administered once daily to both eyes of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were below the lower limit of detection (0.025 ng/mL) in most subjects within 1.5 hours after dosing. Mean Cmax and AUC0-24hr values were similar on days 7 and 14 at approximately 0.08 ng/mL and 0.09 nghr/mL, respectively, indicating that steady state was reached during the first week of ocular dosing. There was no significant systemic drug accumulation over time. - Distribution: Bimatoprost is moderately distributed into body tissues with a steady-state volume of distribution of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Approximately 12% of bimatoprost remains unbound in human plasma. - Metabolism: Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites. - Elimination: Following an intravenous dose of radiolabeled bimatoprost (3.12 mcg/kg) to six healthy subjects, the maximum blood concentration of unchanged drug was 12.2 ng/mL and decreased rapidly with an elimination half-life of approximately 45 minutes. The total blood clearance of bimatoprost was 1.5 L/hr/kg. Up to 67% of the administered dose was excreted in the urine while 25% of the dose was recovered in the feces. ## Nonclinical Toxicology - Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times the recommended human exposure based on blood AUC levels respectively) for 104 weeks. - Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests. - Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (at least 103 times the recommended human exposure based on blood AUC levels). # Clinical Studies - In a 12-month clinical study of patients with open angle glaucoma or ocular hypertension with an average baseline IOP of 23.5 mmHg, the IOP-lowering effect of LUMIGAN® 0.01% once daily (in the evening) was up to 7.5 mmHg. # How Supplied - LUMIGAN® (bimatoprost ophthalmic solution) 0.01% is supplied sterile in opaque white low density polyethylene ophthalmic dispenser bottles and tips with turquoise polystyrene caps in the following sizes: - 2.5 mL fill in a 5 mL container - NDC 0023-3205-03 - 5 mL fill in a 10 mL container - NDC 0023-3205-05 - 7.5 mL fill in a 10 mL container - NDC 0023-3205-08 - Storage: Store at 2°-25°C (36°-77°F). ## Storage There is limited information regarding Bimatoprost Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Potential for Pigmentation - Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of LUMIGAN® (bimatoprost ophthalmic solution) 0.01%. - Potential for Eyelash Changes - Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with LUMIGAN® 0.01%. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. - Handling the Container - Instruct patients to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. - When to Seek Physician Advice - Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of LUMIGAN® 0.01%. - Use with Contact Lenses - Advise patients that LUMIGAN® 0.01% contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of LUMIGAN® 0.01% and may be reinserted 15 minutes following its administration. - Use with Other Ophthalmic Drugs - Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications. # Precautions with Alcohol - Alcohol-Bimatoprost interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LUMIGAN® # Look-Alike Drug Names There is limited information regarding Bimatoprost Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Bimatoprost 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 Bimatoprost is a prostaglandin analog that is FDA approved for the {{{indicationType}}} of open angle glaucoma or ocular hypertension. Common adverse reactions include conjunctival hyperemia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - LUMIGAN® (bimatoprost ophthalmic solution) 0.01% is indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension. - The recommended dosage is one drop in the affected eye(s) once daily in the evening. LUMIGAN® (bimatoprost ophthalmic solution) 0.01% should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect. - Reduction of the intraocular pressure starts approximately 4 hours after the first administration with maximum effect reached within approximately 8 to 12 hours. - LUMIGAN® 0.01% may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bimatoprost in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bimatoprost in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Bimatoprost in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Bimatoprost in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Bimatoprost in pediatric patients. # Contraindications - None # Warnings ### Precautions - Pigmentation - Bimatoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as bimatoprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of bimatoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known. - Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with LUMIGAN® (bimatoprost ophthalmic solution) 0.01% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. - Eyelash Changes - LUMIGAN® 0.01% may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment. - Intraocular Inflammation - Prostaglandin analogs, including bimatoprost, have been reported to cause intraocular inflammation. In addition, because these products may exacerbate inflammation, caution should be used in patients with active intraocular inflammation (e.g., uveitis). - Macular Edema - Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic solution. LUMIGAN® 0.01% should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. - Bacterial Keratitis - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. - Use with Contact Lenses - Contact lenses should be removed prior to instillation of LUMIGAN® 0.01% and may be reinserted 15 minutes following its administration. # 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. - In a 12-month clinical study with bimatoprost ophthalmic solutions 0.01%, the most common adverse reaction was conjunctival hyperemia (31%). Approximately 1.6% of patients discontinued therapy due to conjunctival hyperemia. Other adverse drug reactions (reported in 1 to 4% of patients) with LUMIGAN® 0.01% in this study included conjunctival edema, conjunctival hemorrhage, eye irritation, eye pain, eye pruritus, erythema of eyelid, eyelids pruritus, growth of eyelashes, hypertrichosis, instillation site irritation, punctate keratitis, skin hyperpigmentation, vision blurred, and visual acuity reduced. ## Postmarketing Experience - The following reaction has been identified during postmarketing use of LUMIGAN® 0.01% in clinical practice. Because it was reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reaction, which has been chosen for inclusion due to either its seriousness, frequency of reporting, possible causal connection to LUMIGAN® 0.01%, or a combination of these factors, includes headache. - In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed. # Drug Interactions There is limited information regarding Bimatoprost Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of bimatoprost which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood AUC levels. - At doses at least 41 times the maximum intended human exposure based on blood AUC levels, the gestation length was reduced in the dams, the incidence of dead fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup body weights were reduced. - There are no adequate and well-controlled studies of LUMIGAN® (bimatoprost ophthalmic solution) 0.01% administration in pregnant women. Because animal reproductive studies are not always predictive of human response LUMIGAN® 0.01% should be administered 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 Bimatoprost in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Bimatoprost during labor and delivery. ### Nursing Mothers - It is not known whether LUMIGAN® 0.01% is excreted in human milk, although in animal studies, bimatoprost has been shown to be excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when LUMIGAN® 0.01% is administered to a nursing woman. ### Pediatric Use - Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use. ### Geriatic Use - No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients. ### Gender There is no FDA guidance on the use of Bimatoprost with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bimatoprost with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bimatoprost in patients with renal impairment. ### Hepatic Impairment - In patients with a history of liver disease or abnormal ALT, AST and/or bilirubin at baseline, bimatoprost 0.03% had no adverse effect on liver function over 48 months. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bimatoprost in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bimatoprost in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Bimatoprost in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Bimatoprost in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - No information is available on overdosage in humans. In oral (by gavage) mouse and rat studies, doses up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 210 times higher than the accidental dose of one bottle of LUMIGAN® 0.01% for a 10 kg child. ### Management - If overdose with LUMIGAN® (bimatoprost ophthalmic solution) 0.01% occurs, treatment should be symptomatic. ## Chronic Overdose There is limited information regarding Chronic Overdose of Bimatoprost in the drug label. # Pharmacology ## Mechanism of Action - Bimatoprost, a prostaglandin analog, is a synthetic structural analog of prostaglandin with ocular hypotensive activity. It selectively mimics the effects of naturally occurring substances, prostamides. Bimatoprost is believed to lower intraocular pressure (IOP) in humans by increasing outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Elevated IOP presents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. ## Structure - LUMIGAN® (bimatoprost ophthalmic solution) 0.01% is a synthetic prostamide analog with ocular hypotensive activity. Its chemical name is (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular formula is C25H37NO4. Its chemical structure is: - Bimatoprost is a powder, which is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. LUMIGAN® 0.01% is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg. - LUMIGAN® 0.01% contains Active: bimatoprost 0.1 mg/mL; Inactives: benzalkonium chloride 0.2 mg/mL; sodium chloride; sodium phosphate, dibasic; citric acid; and purified water. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8-7.8. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Bimatoprost in the drug label. ## Pharmacokinetics - Absorption: After one drop of bimatoprost ophthalmic solution 0.03% was administered once daily to both eyes of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were below the lower limit of detection (0.025 ng/mL) in most subjects within 1.5 hours after dosing. Mean Cmax and AUC0-24hr values were similar on days 7 and 14 at approximately 0.08 ng/mL and 0.09 ng•hr/mL, respectively, indicating that steady state was reached during the first week of ocular dosing. There was no significant systemic drug accumulation over time. - Distribution: Bimatoprost is moderately distributed into body tissues with a steady-state volume of distribution of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Approximately 12% of bimatoprost remains unbound in human plasma. - Metabolism: Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites. - Elimination: Following an intravenous dose of radiolabeled bimatoprost (3.12 mcg/kg) to six healthy subjects, the maximum blood concentration of unchanged drug was 12.2 ng/mL and decreased rapidly with an elimination half-life of approximately 45 minutes. The total blood clearance of bimatoprost was 1.5 L/hr/kg. Up to 67% of the administered dose was excreted in the urine while 25% of the dose was recovered in the feces. ## Nonclinical Toxicology - Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times the recommended human exposure based on blood AUC levels respectively) for 104 weeks. - Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests. - Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (at least 103 times the recommended human exposure based on blood AUC levels). # Clinical Studies - In a 12-month clinical study of patients with open angle glaucoma or ocular hypertension with an average baseline IOP of 23.5 mmHg, the IOP-lowering effect of LUMIGAN® 0.01% once daily (in the evening) was up to 7.5 mmHg. # How Supplied - LUMIGAN® (bimatoprost ophthalmic solution) 0.01% is supplied sterile in opaque white low density polyethylene ophthalmic dispenser bottles and tips with turquoise polystyrene caps in the following sizes: - 2.5 mL fill in a 5 mL container - NDC 0023-3205-03 - 5 mL fill in a 10 mL container - NDC 0023-3205-05 - 7.5 mL fill in a 10 mL container - NDC 0023-3205-08 - Storage: Store at 2°-25°C (36°-77°F). ## Storage There is limited information regarding Bimatoprost Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Potential for Pigmentation - Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of LUMIGAN® (bimatoprost ophthalmic solution) 0.01%. - Potential for Eyelash Changes - Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with LUMIGAN® 0.01%. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. - Handling the Container - Instruct patients to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. - When to Seek Physician Advice - Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of LUMIGAN® 0.01%. - Use with Contact Lenses - Advise patients that LUMIGAN® 0.01% contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of LUMIGAN® 0.01% and may be reinserted 15 minutes following its administration. - Use with Other Ophthalmic Drugs - Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications. # Precautions with Alcohol - Alcohol-Bimatoprost interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - LUMIGAN®[1] # Look-Alike Drug Names There is limited information regarding Bimatoprost Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Bimatoprost
988247553dda97bb1da058092687e415aced7ff2	wikidoc	Binimetinib	Binimetinib # 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 Binimetinib is a kinase inhibitor that is FDA approved for the treatment of patients, in combination with encorafenib, with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Common adverse reactions include fatigue, nausea, diarrhea, vomiting, and abdominal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Binimetinib is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Dosage - The recommended dose is 45 mg orally twice daily in combination with encorafenib. Take binimetinib with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding binimetinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding binimetinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of binimetinib have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding binimetinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding binimetinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with binimetinib in combination with encorafenib. In COLUMBUS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥ 10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving binimetinib plus encorafenib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving binimetinib in combination with encorafenib was 3.6 months (range 0 to 21 months). Cardiomyopathy resolved in 87% of patients receiving binimetinib plus encorafenib. - Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every 2 to 3 months during treatment. The safety of binimetinib in combination with encorafenib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with binimetinib. - Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - In COLUMBUS, venous thromboembolism (VTE) occurred in 6% of patients receiving binimetinib in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Serous Retinopathy - In COLUMBUS, serous retinopathy occurred in 20% of patients treated with binimetinib in combination with encorafenib; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. No patient discontinued binimetinib due to serous retinopathy; 6% of patients required dose interruptions or dose reductions. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months (range 0 to 17.5 months). - Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Retinal Vein Occlusion - RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with binimetinib in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving binimetinib with encorafenib (n=690), 1 patient experienced RVO (0.1%). - The safety of binimetinib has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. - Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue binimetinib in patients with documented RVO. Uveitis - Uveitis, including iritis and iridocyclitis, has been reported in patients treated with binimetinib in combination with encorafenib. In COLUMBUS, the incidence of uveitis among patients treated with binimetinib in combination with encorafenib was 4%. - Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - In patients with BRAF mutation-positive melanoma receiving binimetinib with encorafenib (n=690), 2 patients (0.3%) developed interstitial lung disease (ILD), including pneumonitis. - Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Hepatotoxicity can occur when binimetinib is administered in combination with encorafenib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving binimetinib in combination with encorafenib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. - Monitor liver laboratory tests before initiation of binimetinib, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Rhabdomyolysis can occur when binimetinib is administered in combination with encorafenib. In COLUMBUS, elevation of laboratory values of serum CPK occurred in 58% of patients treated with binimetinib in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving binimetinib with encorafenib (n=690), rhabdomyolysis was reported in 1 patient (0.1%). - Monitor CPK and creatinine levels prior to initiating binimetinib, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Hemorrhage can occur when binimetinib is administered in combination with encorafenib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving binimetinib in combination with encorafenib. Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. - Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Based on findings from animal studies and its mechanism of action, binimetinib can cause fetal harm when administered to a pregnant woman. Binimetinib was embryotoxic and abortifacient when administered to rabbits during the period of organogenesis at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the recommended clinical dose of 45 mg twice daily. - Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with binimetinib and for at least 30 days after the final dose. - Binimetinib is indicated for use in combination with encorafenib. Refer to the encorafenib prescribing information for additional risk information that applies to combination use treatment. # 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 data described in Warnings and Precautions reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to binimetinib (45 mg twice daily) in combination with encorafenib (450 mg once daily) in a randomized open-label, active-controlled trial (COLUMBUS) or, for rare events, exposure of 690 patients with BRAF V600 mutation-positive melanoma to binimetinib (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials. - The data described below reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to binimetinib (45 mg twice daily) in combination with encorafenib (450 mg once daily) in COLUMBUS. - The COLUMBUS trial excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with binimetinib in combination with encorafenib and 6.2 months for patients treated with vemurafenib. - The most common (≥ 25%) adverse reactions in patients receiving binimetinib in combination with encorafenib were fatigue, nausea, diarrhea, vomiting, and abdominal pain. - Adverse reactions leading to dose interruptions of binimetinib occurred in 33% of patients receiving binimetinib in combination with encorafenib; the most common were left ventricular dysfunction (6%) and serous retinopathy (5%). Adverse reactions leading to dose reductions of binimetinib occurred in 19% of patients receiving binimetinib in combination with encorafenib; the most common were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%). Five percent (5%) of patients receiving binimetinib in combination with encorafenib experienced an adverse reaction that resulted in permanent discontinuation of binimetinib. The most common adverse reactions resulting in permanent discontinuation of binimetinib were hemorrhage in 2% and headache in 1% of patients. - Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for binimetinib in combination with encorafenib, as compared to vemurafenib, for any specific adverse reaction listed in Table 3. - Other clinically important adverse reactions occurring in < 10% of patients who received binimetinib in combination with encorafenib were: Gastrointestinal disorders: Colitis Skin and subcutaneous tissue disorders: Panniculitis Immune system disorders: Drug hypersensitivity - Gastrointestinal disorders: Colitis - Skin and subcutaneous tissue disorders: Panniculitis - Immune system disorders: Drug hypersensitivity ## Postmarketing Experience There is limited information regarding Binimetinib Postmarketing Experience in the drug label. # Drug Interactions - No clinically important drug interactions have been observed with binimetinib. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on findings from animal reproduction studies and its mechanism of action, binimetinib can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of binimetinib during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the clinical dose of 45 mg twice daily. Advise pregnant women of the potential risk to a fetus. - 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. Animal Data - In reproductive toxicity studies, administration of binimetinib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights and increased variations in ossification at doses ≥ 30 mg/kg/day (approximately 37 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). In pregnant rabbits, administration of binimetinib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, an increase in malformations, and increased post-implantation loss, including total loss of pregnancy at doses ≥ 10 mg/kg/day (approximately 5 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). There was a significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/day of binimetinib (less than 8 times the human exposure at the recommended clinical dose of 45 mg twice daily). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Binimetinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Binimetinib during labor and delivery. ### Nursing Mothers Risk Summary - There are no data on the presence of binimetinib or its active metabolite in human milk, or the effects of binimetinib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from binimetinib in breastfed infants, advise women not to breastfeed during treatment with binimetinib and for 3 days after the final dose. ### Pediatric Use - The safety and effectiveness of binimetinib have not been established in pediatric patients. ### Geriatic Use - Of the 690 patients with BRAF mutation-positive melanoma who received binimetinib (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in the safety or effectiveness of binimetinib plus encorafenib were observed in elderly patients as compared to younger patients. ### Gender There is no FDA guidance on the use of Binimetinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Binimetinib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Binimetinib in patients with renal impairment. ### Hepatic Impairment - Binimetinib concentrations may increase in patients with moderate or severe hepatic impairment. Dose adjustment for binimetinib is not recommended in patients with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN). Reduce the dose of binimetinib for patients with moderate (total bilirubin > 1.5 and ≤ 3 × ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment. ### Females of Reproductive Potential and Males Pregnancy Testing - Verify the pregnancy status of females of reproductive potential prior to initiating binimetinib. Contraception - Binimetinib can cause fetal harm when administered to a pregnant woman. Females - Advise females of reproductive potential to use effective contraception during treatment with binimetinib and for at least 30 days after the final dose. ### Immunocompromised Patients There is no FDA guidance one the use of Binimetinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating binimetinib. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: . - The recommended dosage of binimetinib is 45 mg orally taken twice daily, approximately 12 hours apart, in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosing information. - Binimetinib may be taken with or without food. Do not take a missed dose of binimetinib within 6 hours of the next dose of binimetinib. - Do not take an additional dose if vomiting occurs after binimetinib administration but continue with the next scheduled dose. - If encorafenib is permanently discontinued, discontinue binimetinib. - Dose reductions for adverse reactions associated with binimetinib are presented in Table 1. - Dosage modifications for adverse reactions associated with binimetinib are presented in Table 2. - Refer to the encorafenib prescribing information for dose modifications for adverse reactions associated with encorafenib. - For patients with moderate (total bilirubin greater than 1.5 and less than or equal to 3 × ULN and any AST) or severe (total bilirubin levels greater than 3 × ULN and any AST) hepatic impairment, the recommended dosage is 30 mg orally taken twice daily. ### Monitoring There is limited information regarding Binimetinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Binimetinib and IV administrations. # Overdosage - Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with binimetinib. # Pharmacology ## Mechanism of Action - Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models. - Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. ## Structure The molecular formula is C17H15BrF2N4O3 and the molecular weight is 441.2 daltons. The chemical structure of binimetinib is shown below: ## Pharmacodynamics Cardiac Electrophysiology - Following binimetinib 45 mg twice daily, no clinically meaningful QT prolongation was observed. ## Pharmacokinetics - The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is < 40% at steady state. The systemic exposure of binimetinib is approximately dose proportional. Absorption - After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (Tmax) of 1.6 hours. Effect of Food - The administration of a single dose of binimetinib 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure. Distribution - Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%). Elimination - The mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F) is 20.2 L/h (24%). Metabolism - The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib. Excretion - Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the urine. Specific Populations - Age (20 to 94 years), sex, or body weight do not have a clinically important effect on the systemic exposure of binimetinib. The effect of race or ethnicity on the pharmacokinetics of binimetinib is unknown. - Hepatic Impairment: No clinically meaningful changes in binimetinib exposure (AUC and Cmax) were observed in subjects with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) as compared to subjects with normal liver function (total bilirubin ≤ ULN and AST ≤ ULN). A 2-fold increase in AUC was observed in subjects with moderate (total bilirubin > 1.5 and ≤ 3 × ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment. - Renal Impairment: In subjects with severe renal impairment (eGFR ≤ 29 mL/min/1.73 m2), no clinically important changes in binimetinib exposure were observed as compared to subjects with normal renal function. Drug Interaction Studies Clinical Studies - Effect of UGT1A1 Inducers or Inhibitors on Binimetinib: UGT1A1 genotype and smoking (UGT1A1 inducer) do not have a clinically important effect on binimetinib exposure. Simulations predict similar Cmax of binimetinib 45 mg in the presence or absence of atazanavir 400 mg (UGT1A1 inhibitor). - No differences in binimetinib exposure have been observed when binimetinib is coadministered with encorafenib. - Effect of Binimetinib on CYP Substrates: Binimetinib did not alter the exposure of a sensitive CYP3A4 substrate (midazolam). - Effect of Acid Reducing Agents on Binimetinib: The extent of binimetinib exposure (AUC) was not altered in the presence of a gastric acid reducing agent (rabeprazole). In Vitro Studies - Effect of Binimetinib on CYP Substrates: Binimetinib is not a time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A. - Effect of Transporters on Binimetinib: Binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Binimetinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) or organic cation transporter 1 (OCT1). ## Nonclinical Toxicology - Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats. - No dedicated fertility studies have been conducted with binimetinib in animals. In general toxicology studies in rats and monkeys, there were no remarkable findings in male or female reproductive organs. # Clinical Studies - Binimetinib in combination with encorafenib was evaluated in a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no). - Patients were randomized (1:1:1) to receive binimetinib 45 mg twice daily in combination with encorafenib 450 mg once daily (binimetinib in combination with encorafenib), encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (binimetinib 45 mg in combination with encorafenib 450 mg) are described below. - The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent central review, to compare binimetinib in combination with encorafenib with vemurafenib. Additional efficacy measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review. - A total of 577 patients were randomized, 192 to the binimetinib in combination with encorafenib arm, 194 to the encorafenib arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the binimetinib in combination with encorafenib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had ≥ 3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients' tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (< 1%). - Binimetinib in combination with encorafenib demonstrated a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 5 and Figure 1. # How Supplied - Binimetinib is supplied as 15 mg yellow/dark yellow, unscored biconvex oval film-coated tablets debossed with a stylized "A" on one side and "15" on the other side, available in bottles of 180 tablets. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Patient Information). - Inform patients of the following: Cardiomyopathy - Advise patients to report any symptoms of heart failure to their healthcare provider. Venous Thrombosis - Advise patients to contact their healthcare provider if they experience symptoms of venous thrombosis or pulmonary embolism. Advise patients to seek medical attention for sudden onset of difficulty breathing, leg pain, or swelling. Ocular Toxicities - Advise patients to contact their healthcare provider if they experience any changes in their vision. Interstitial Lung Disease - Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including cough or dyspnea. Hepatotoxicity - Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with binimetinib. Instruct patients to report symptoms of liver dysfunction including jaundice, dark urine, nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding. Rhabdomyolysis - Advise patients to contact their healthcare provider as soon as possible if they experience unusual or new onset weakness, myalgia, or darkened urine. Hemorrhage - Advise patients to notify their healthcare provider if they experience symptoms suggestive of hemorrhage, such as unusual bleeding. Females and Males of Reproductive Potential - Embryo-Fetal Toxicity: Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with binimetinib and for 30 days after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with binimetinib. - Lactation: Advise women not to breastfeed during treatment with binimetinib and for 3 days after the final dose. # Precautions with Alcohol Alcohol-Binimetinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Mektovi # Look-Alike Drug Names There is limited information regarding Binimetinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Binimetinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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 Binimetinib is a kinase inhibitor that is FDA approved for the treatment of patients, in combination with encorafenib, with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Common adverse reactions include fatigue, nausea, diarrhea, vomiting, and abdominal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Binimetinib is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Dosage - The recommended dose is 45 mg orally twice daily in combination with encorafenib. Take binimetinib with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding binimetinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding binimetinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of binimetinib have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding binimetinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding binimetinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with binimetinib in combination with encorafenib. In COLUMBUS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥ 10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving binimetinib plus encorafenib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving binimetinib in combination with encorafenib was 3.6 months (range 0 to 21 months). Cardiomyopathy resolved in 87% of patients receiving binimetinib plus encorafenib. - Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every 2 to 3 months during treatment. The safety of binimetinib in combination with encorafenib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with binimetinib. - Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - In COLUMBUS, venous thromboembolism (VTE) occurred in 6% of patients receiving binimetinib in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Serous Retinopathy - In COLUMBUS, serous retinopathy occurred in 20% of patients treated with binimetinib in combination with encorafenib; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. No patient discontinued binimetinib due to serous retinopathy; 6% of patients required dose interruptions or dose reductions. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months (range 0 to 17.5 months). - Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Retinal Vein Occlusion - RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with binimetinib in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving binimetinib with encorafenib (n=690), 1 patient experienced RVO (0.1%). - The safety of binimetinib has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. - Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue binimetinib in patients with documented RVO. Uveitis - Uveitis, including iritis and iridocyclitis, has been reported in patients treated with binimetinib in combination with encorafenib. In COLUMBUS, the incidence of uveitis among patients treated with binimetinib in combination with encorafenib was 4%. - Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - In patients with BRAF mutation-positive melanoma receiving binimetinib with encorafenib (n=690), 2 patients (0.3%) developed interstitial lung disease (ILD), including pneumonitis. - Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Hepatotoxicity can occur when binimetinib is administered in combination with encorafenib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving binimetinib in combination with encorafenib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. - Monitor liver laboratory tests before initiation of binimetinib, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Rhabdomyolysis can occur when binimetinib is administered in combination with encorafenib. In COLUMBUS, elevation of laboratory values of serum CPK occurred in 58% of patients treated with binimetinib in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving binimetinib with encorafenib (n=690), rhabdomyolysis was reported in 1 patient (0.1%). - Monitor CPK and creatinine levels prior to initiating binimetinib, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Hemorrhage can occur when binimetinib is administered in combination with encorafenib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving binimetinib in combination with encorafenib. Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. - Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Based on findings from animal studies and its mechanism of action, binimetinib can cause fetal harm when administered to a pregnant woman. Binimetinib was embryotoxic and abortifacient when administered to rabbits during the period of organogenesis at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the recommended clinical dose of 45 mg twice daily. - Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with binimetinib and for at least 30 days after the final dose. - Binimetinib is indicated for use in combination with encorafenib. Refer to the encorafenib prescribing information for additional risk information that applies to combination use treatment. # 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 data described in Warnings and Precautions reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to binimetinib (45 mg twice daily) in combination with encorafenib (450 mg once daily) in a randomized open-label, active-controlled trial (COLUMBUS) or, for rare events, exposure of 690 patients with BRAF V600 mutation-positive melanoma to binimetinib (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials. - The data described below reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to binimetinib (45 mg twice daily) in combination with encorafenib (450 mg once daily) in COLUMBUS. - The COLUMBUS trial excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with binimetinib in combination with encorafenib and 6.2 months for patients treated with vemurafenib. - The most common (≥ 25%) adverse reactions in patients receiving binimetinib in combination with encorafenib were fatigue, nausea, diarrhea, vomiting, and abdominal pain. - Adverse reactions leading to dose interruptions of binimetinib occurred in 33% of patients receiving binimetinib in combination with encorafenib; the most common were left ventricular dysfunction (6%) and serous retinopathy (5%). Adverse reactions leading to dose reductions of binimetinib occurred in 19% of patients receiving binimetinib in combination with encorafenib; the most common were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%). Five percent (5%) of patients receiving binimetinib in combination with encorafenib experienced an adverse reaction that resulted in permanent discontinuation of binimetinib. The most common adverse reactions resulting in permanent discontinuation of binimetinib were hemorrhage in 2% and headache in 1% of patients. - Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for binimetinib in combination with encorafenib, as compared to vemurafenib, for any specific adverse reaction listed in Table 3. - Other clinically important adverse reactions occurring in < 10% of patients who received binimetinib in combination with encorafenib were: Gastrointestinal disorders: Colitis Skin and subcutaneous tissue disorders: Panniculitis Immune system disorders: Drug hypersensitivity - Gastrointestinal disorders: Colitis - Skin and subcutaneous tissue disorders: Panniculitis - Immune system disorders: Drug hypersensitivity ## Postmarketing Experience There is limited information regarding Binimetinib Postmarketing Experience in the drug label. # Drug Interactions - No clinically important drug interactions have been observed with binimetinib. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on findings from animal reproduction studies and its mechanism of action, binimetinib can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of binimetinib during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the clinical dose of 45 mg twice daily. Advise pregnant women of the potential risk to a fetus. - 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. Animal Data - In reproductive toxicity studies, administration of binimetinib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights and increased variations in ossification at doses ≥ 30 mg/kg/day (approximately 37 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). In pregnant rabbits, administration of binimetinib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, an increase in malformations, and increased post-implantation loss, including total loss of pregnancy at doses ≥ 10 mg/kg/day (approximately 5 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). There was a significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/day of binimetinib (less than 8 times the human exposure at the recommended clinical dose of 45 mg twice daily). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Binimetinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Binimetinib during labor and delivery. ### Nursing Mothers Risk Summary - There are no data on the presence of binimetinib or its active metabolite in human milk, or the effects of binimetinib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from binimetinib in breastfed infants, advise women not to breastfeed during treatment with binimetinib and for 3 days after the final dose. ### Pediatric Use - The safety and effectiveness of binimetinib have not been established in pediatric patients. ### Geriatic Use - Of the 690 patients with BRAF mutation-positive melanoma who received binimetinib (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in the safety or effectiveness of binimetinib plus encorafenib were observed in elderly patients as compared to younger patients. ### Gender There is no FDA guidance on the use of Binimetinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Binimetinib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Binimetinib in patients with renal impairment. ### Hepatic Impairment - Binimetinib concentrations may increase in patients with moderate or severe hepatic impairment. Dose adjustment for binimetinib is not recommended in patients with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN). Reduce the dose of binimetinib for patients with moderate (total bilirubin > 1.5 and ≤ 3 × ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment. ### Females of Reproductive Potential and Males Pregnancy Testing - Verify the pregnancy status of females of reproductive potential prior to initiating binimetinib. Contraception - Binimetinib can cause fetal harm when administered to a pregnant woman. Females - Advise females of reproductive potential to use effective contraception during treatment with binimetinib and for at least 30 days after the final dose. ### Immunocompromised Patients There is no FDA guidance one the use of Binimetinib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating binimetinib. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. - The recommended dosage of binimetinib is 45 mg orally taken twice daily, approximately 12 hours apart, in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosing information. - Binimetinib may be taken with or without food. Do not take a missed dose of binimetinib within 6 hours of the next dose of binimetinib. - Do not take an additional dose if vomiting occurs after binimetinib administration but continue with the next scheduled dose. - If encorafenib is permanently discontinued, discontinue binimetinib. - Dose reductions for adverse reactions associated with binimetinib are presented in Table 1. - Dosage modifications for adverse reactions associated with binimetinib are presented in Table 2. - Refer to the encorafenib prescribing information for dose modifications for adverse reactions associated with encorafenib. - For patients with moderate (total bilirubin greater than 1.5 and less than or equal to 3 × ULN and any AST) or severe (total bilirubin levels greater than 3 × ULN and any AST) hepatic impairment, the recommended dosage is 30 mg orally taken twice daily. ### Monitoring There is limited information regarding Binimetinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Binimetinib and IV administrations. # Overdosage - Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with binimetinib. # Pharmacology ## Mechanism of Action - Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models. - Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. ## Structure The molecular formula is C17H15BrF2N4O3 and the molecular weight is 441.2 daltons. The chemical structure of binimetinib is shown below: ## Pharmacodynamics Cardiac Electrophysiology - Following binimetinib 45 mg twice daily, no clinically meaningful QT prolongation was observed. ## Pharmacokinetics - The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is < 40% at steady state. The systemic exposure of binimetinib is approximately dose proportional. Absorption - After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (Tmax) of 1.6 hours. Effect of Food - The administration of a single dose of binimetinib 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure. Distribution - Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is 0.72. The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%). Elimination - The mean (CV%) terminal half-life (t1/2) of binimetinib is 3.5 hours (28.5%) and apparent clearance (CL/F) is 20.2 L/h (24%). Metabolism - The primary metabolic pathway is glucuronidation with UGT1A1 contributing up to 61% of the binimetinib metabolism. Other pathways of binimetinib metabolism include N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 produced by CYP1A2 and CYP2C19 represents 8.6% of the binimetinib exposure. Following a single oral dose of 45 mg radiolabeled binimetinib, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib. Excretion - Following a single oral dose of 45 mg radiolabeled binimetinib in healthy subjects, 62% (32% unchanged) of the administered dose was recovered in the feces while 31% (6.5% unchanged) was recovered in the urine. Specific Populations - Age (20 to 94 years), sex, or body weight do not have a clinically important effect on the systemic exposure of binimetinib. The effect of race or ethnicity on the pharmacokinetics of binimetinib is unknown. - Hepatic Impairment: No clinically meaningful changes in binimetinib exposure (AUC and Cmax) were observed in subjects with mild hepatic impairment (total bilirubin > 1 and ≤ 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) as compared to subjects with normal liver function (total bilirubin ≤ ULN and AST ≤ ULN). A 2-fold increase in AUC was observed in subjects with moderate (total bilirubin > 1.5 and ≤ 3 × ULN and any AST) or severe (total bilirubin levels > 3 × ULN and any AST) hepatic impairment. - Renal Impairment: In subjects with severe renal impairment (eGFR ≤ 29 mL/min/1.73 m2), no clinically important changes in binimetinib exposure were observed as compared to subjects with normal renal function. Drug Interaction Studies Clinical Studies - Effect of UGT1A1 Inducers or Inhibitors on Binimetinib: UGT1A1 genotype and smoking (UGT1A1 inducer) do not have a clinically important effect on binimetinib exposure. Simulations predict similar Cmax of binimetinib 45 mg in the presence or absence of atazanavir 400 mg (UGT1A1 inhibitor). - No differences in binimetinib exposure have been observed when binimetinib is coadministered with encorafenib. - Effect of Binimetinib on CYP Substrates: Binimetinib did not alter the exposure of a sensitive CYP3A4 substrate (midazolam). - Effect of Acid Reducing Agents on Binimetinib: The extent of binimetinib exposure (AUC) was not altered in the presence of a gastric acid reducing agent (rabeprazole). In Vitro Studies - Effect of Binimetinib on CYP Substrates: Binimetinib is not a time-dependent inhibitor of CYP1A2, CYP2C9, CYP2D6 or CYP3A. - Effect of Transporters on Binimetinib: Binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Binimetinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1) or organic cation transporter 1 (OCT1). ## Nonclinical Toxicology - Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats. - No dedicated fertility studies have been conducted with binimetinib in animals. In general toxicology studies in rats and monkeys, there were no remarkable findings in male or female reproductive organs. # Clinical Studies - Binimetinib in combination with encorafenib was evaluated in a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no). - Patients were randomized (1:1:1) to receive binimetinib 45 mg twice daily in combination with encorafenib 450 mg once daily (binimetinib in combination with encorafenib), encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (binimetinib 45 mg in combination with encorafenib 450 mg) are described below. - The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent central review, to compare binimetinib in combination with encorafenib with vemurafenib. Additional efficacy measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review. - A total of 577 patients were randomized, 192 to the binimetinib in combination with encorafenib arm, 194 to the encorafenib arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the binimetinib in combination with encorafenib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had ≥ 3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients' tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (< 1%). - Binimetinib in combination with encorafenib demonstrated a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 5 and Figure 1. # How Supplied - Binimetinib is supplied as 15 mg yellow/dark yellow, unscored biconvex oval film-coated tablets debossed with a stylized "A" on one side and "15" on the other side, available in bottles of 180 tablets. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Patient Information). - Inform patients of the following: Cardiomyopathy - Advise patients to report any symptoms of heart failure to their healthcare provider. Venous Thrombosis - Advise patients to contact their healthcare provider if they experience symptoms of venous thrombosis or pulmonary embolism. Advise patients to seek medical attention for sudden onset of difficulty breathing, leg pain, or swelling. Ocular Toxicities - Advise patients to contact their healthcare provider if they experience any changes in their vision. Interstitial Lung Disease - Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including cough or dyspnea. Hepatotoxicity - Advise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with binimetinib. Instruct patients to report symptoms of liver dysfunction including jaundice, dark urine, nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding. Rhabdomyolysis - Advise patients to contact their healthcare provider as soon as possible if they experience unusual or new onset weakness, myalgia, or darkened urine. Hemorrhage - Advise patients to notify their healthcare provider if they experience symptoms suggestive of hemorrhage, such as unusual bleeding. Females and Males of Reproductive Potential - Embryo-Fetal Toxicity: Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with binimetinib and for 30 days after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with binimetinib. - Lactation: Advise women not to breastfeed during treatment with binimetinib and for 3 days after the final dose. # Precautions with Alcohol Alcohol-Binimetinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Mektovi # Look-Alike Drug Names There is limited information regarding Binimetinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Binimetinib
54244712f9309336eec041611748e51e8c80274f	wikidoc	Bioisostere	Bioisostere In medicinal chemistry, bioisosteres are substituents or groups with similar physical or chemical properties that impart similar biological properties to a chemical compound. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure. For example, the replacement of a hydrogen atom with a fluorine atom at a site of metabolic oxidation in a drug candidate may prevent such metabolism from taking place. Because the fluorine atom is similar in size to the hydrogen atom the overall topology of the molecule is not significantly affected, leaving the desired biological activity unaffected. However, with a blocked pathway for metabolism, the drug candidate may have a longer half-life. There are many examples of bioisosteres, which may be equivalent in some instances but not in others depending on what factors are important in binding (electronegativity, size, polarity etc). So for instance a chlorine -Cl group may often be replaced by a trifluoromethyl -CF3 group, or by a cyano -CN group, but depending on the particular molecule used the substitution may result in little change in activity, or either increase or decrease affinity or efficacy depending on what factors are important for target binding. Another example is aromatic rings, a phenyl -C6H5 ring can often be replaced by a different aromatic ring such as thiophene or naphthalene which may either improve efficacy or change specificity of binding.	Bioisostere In medicinal chemistry, bioisosteres are substituents or groups with similar physical or chemical properties that impart similar biological properties to a chemical compound. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure. For example, the replacement of a hydrogen atom with a fluorine atom at a site of metabolic oxidation in a drug candidate may prevent such metabolism from taking place. Because the fluorine atom is similar in size to the hydrogen atom the overall topology of the molecule is not significantly affected, leaving the desired biological activity unaffected. However, with a blocked pathway for metabolism, the drug candidate may have a longer half-life. There are many examples of bioisosteres, which may be equivalent in some instances but not in others depending on what factors are important in binding (electronegativity, size, polarity etc). So for instance a chlorine -Cl group may often be replaced by a trifluoromethyl -CF3 group, or by a cyano -CN group, but depending on the particular molecule used the substitution may result in little change in activity, or either increase or decrease affinity or efficacy depending on what factors are important for target binding. Another example is aromatic rings, a phenyl -C6H5 ring can often be replaced by a different aromatic ring such as thiophene or naphthalene which may either improve efficacy or change specificity of binding.	https://www.wikidoc.org/index.php/Bioisostere
fb585b8d6c394e7db9faccefe4d90cc23ffcc843	wikidoc	Biomolecule	Biomolecule # Overview A biomolecule is a molecule that naturally occurs in living organisms. Biomolecules consist primarily of carbon and hydrogen, along with nitrogen, oxygen, phosphorus and sulfur. Other elements sometimes are incorporated but are much less common. # Explanation All known forms of life are composed solely of biomolecules. For example, humans possess skin and hair. The main component of hair is keratin, an agglomeration of proteins which are themselves polymers built from amino acids. Amino acids are some of the most important building blocks used in nature to construct larger molecules. Another type of building block are the nucleotides, each of which consists of three components: either a purine or pyrimidine base, a pentose sugar and a phosphate group. These nucleotides mainly form the nucleic acids. Besides the polymeric biomolecules, numerous organic molecules are absorbed by living systems. # Types of biomolecules A diverse range of biomolecules exist, including: - Small molecules: Lipid, Phospholipid, Glycolipid, Sterol Vitamin Hormone, Neurotransmitter Carbohydrate, Sugar Disaccharide - Lipid, Phospholipid, Glycolipid, Sterol - Vitamin - Hormone, Neurotransmitter - Carbohydrate, Sugar - Disaccharide - Monomers: Amino acid Nucleotide Phosphate Monosaccharide - Amino acid - Nucleotide - Phosphate - Monosaccharide - Polymers: Peptide, Oligopeptide, Polypeptide, Protein Nucleic acid, i.e. DNA, RNA Oligosaccharide, Polysaccharide - Peptide, Oligopeptide, Polypeptide, Protein - Nucleic acid, i.e. DNA, RNA - Oligosaccharide, Polysaccharide # Nucleosides and nucleotides ## Nucleosides Nucleosides are molecules formed by attaching a nucleobase to a ribose ring. Examples of these include cytidine, uridine, adenosine, guanosine, thymidine and inosine. Nucleosides can be phosphorylated by specific kinases in the cell, producing nucleotides, which are the molecular building blocks of DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). ## Saccharides Monosaccharides are carbohydrates in the form of simple sugars. Examples of monosaccharides are the hexoses glucose, fructose, and galactose and pentoses, ribose, and deoxyribose Disaccharides are formed from two monosaccharides joined together. Examples of disaccharides include sucrose, maltose, and lactose Monosaccharides and disaccharides are sweet, water soluble, and crystalline. Polysaccharides are polymerized monosaccharides, complex, unsweet carbohydrates. Examples are starch, cellulose, and glycogen. They are generally large and often have a complex, branched, connectivity. They are insoluble in water and do not form crystals. Shorter polysaccharides, with 2-15 monomers, are sometimes known as oligosaccharides. ## Lipids Lipids are chiefly fatty acid esters, and are the basic building blocks of biological membranes. Another biological role is energy storage (e.g., triglycerides). Most lipids consist of a polar or hydrophilic head (typically glycerol) and one to three nonpolar or hydrophobic fatty acid tails, and therefore they are amphiphilic. Fatty acids consist of unbranched chains of carbon atoms that are connected by single bonds alone (saturated fatty acids) or by both single and double bonds (unsaturated fatty acids). The chains are usually 14-24 carbon groups long, but it is always an even number. For lipids present in biological membranes, the hydrophilic head is from one of three classes: - Glycolipids, whose heads contain an oligosaccharide with 1-15 saccharide residues. - Phospholipids, whose heads contain a positively charged group that is linked to the tail by a negatively charged phosphate group. - Sterols, whose heads contain a planar steroid ring, for example, cholesterol. Other lipids include prostaglandins and leukotrienes which are both 20-carbon fatty acyl units synthesized from arachidonic acid. They are also known as fatty acids # Hormones Hormones are produced in the endocrine glands, where they are secreted into the bloodstream. They perform a wide range of roles in the various organs including the regulation of metabolic pathways and the regulation of membrane transport processes. Hormones may be grouped into three structural classes: - The steroids are one class of such hormones. They perform a variety of functions, but they are all made from cholesterol. - Simple amines or amino acids. - Peptides or proteins. # Amino acids Amino acids are molecules that contain both amino and carboxylic acid functional groups. (In biochemistry, the term amino acid is used when referring to those amino acids in which the amino and carboxylate functionalities are attached to the same carbon, plus proline which is not actually an amino acid). Amino acids are the building blocks of long polymer chains. With 2-10 amino acids such chains are called peptides, with 10-100 they are often called polypeptides, and longer chains are known as proteins. These protein structures have many structural and functional roles in organisms. There are twenty amino acids that are encoded by the standard genetic code, but there are more than 500 natural amino acids. When amino acids other than the set of twenty are observed in proteins, this is usually the result of modification after translation (protein synthesis). Only two amino acids other than the standard twenty are known to be incorporated into proteins during translation, in certain organisms: - Selenocysteine is incorporated into some proteins at a UGA codon, which is normally a stop codon. - Pyrrolysine is incorporated into some proteins at a UAG codon. For instance, in some methanogens in enzymes that are used to produce methane. Besides those used in protein synthesis, other biologically important amino acids include carnitine (used in lipid transport within a cell), ornithine, GABA and taurine. ## Protein structure The particular series of amino acids that form a protein is known as that protein's primary structure. Proteins have several, well-classified, elements of local structure and these are termed secondary structure. The overall 3D structure of a protein is termed its tertiary structure. Proteins often aggregate into macromolecular structures, or quaternary structure. ### Metalloproteins A metalloprotein is a molecule that contains a metal cofactor. The metal attached to the protein may be an isolated ion or may be a complex organometallic compound or organic compound, such as the porphyrin group found in hemoproteins. In some cases, the metal is coordinated with both a side chain of the protein and an inorganic nonmetallic ion. This type of protein-metal-nonmetal structure is found in iron-sulfur clusters. # Vitamins A vitamin is a compound that cannot be synthesized by a given organism but is nonetheless vital to its survival or health (for example coenzymes). These compounds must be absorbed, or eaten, but typically only in trace quantities. When originally discovered by a Polish doctor, he believed them to all be basic. He therefore named them vital amines. The l was dropped to form the word vitamines.	Biomolecule Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A biomolecule is a molecule that naturally occurs in living organisms. Biomolecules consist primarily of carbon and hydrogen, along with nitrogen, oxygen, phosphorus and sulfur. Other elements sometimes are incorporated but are much less common. # Explanation All known forms of life are composed solely of biomolecules. For example, humans possess skin and hair. The main component of hair is keratin, an agglomeration of proteins which are themselves polymers built from amino acids. Amino acids are some of the most important building blocks used in nature to construct larger molecules. Another type of building block are the nucleotides, each of which consists of three components: either a purine or pyrimidine base, a pentose sugar and a phosphate group. These nucleotides mainly form the nucleic acids. Besides the polymeric biomolecules, numerous organic molecules are absorbed by living systems. # Types of biomolecules A diverse range of biomolecules exist, including: - Small molecules: Lipid, Phospholipid, Glycolipid, Sterol Vitamin Hormone, Neurotransmitter Carbohydrate, Sugar Disaccharide - Lipid, Phospholipid, Glycolipid, Sterol - Vitamin - Hormone, Neurotransmitter - Carbohydrate, Sugar - Disaccharide - Monomers: Amino acid Nucleotide Phosphate Monosaccharide - Amino acid - Nucleotide - Phosphate - Monosaccharide - Polymers: Peptide, Oligopeptide, Polypeptide, Protein Nucleic acid, i.e. DNA, RNA Oligosaccharide, Polysaccharide - Peptide, Oligopeptide, Polypeptide, Protein - Nucleic acid, i.e. DNA, RNA - Oligosaccharide, Polysaccharide # Nucleosides and nucleotides ## Nucleosides Nucleosides are molecules formed by attaching a nucleobase to a ribose ring. Examples of these include cytidine, uridine, adenosine, guanosine, thymidine and inosine. Nucleosides can be phosphorylated by specific kinases in the cell, producing nucleotides, which are the molecular building blocks of DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). ## Saccharides Monosaccharides are carbohydrates in the form of simple sugars. Examples of monosaccharides are the hexoses glucose, fructose, and galactose and pentoses, ribose, and deoxyribose Disaccharides are formed from two monosaccharides joined together. Examples of disaccharides include sucrose, maltose, and lactose Monosaccharides and disaccharides are sweet, water soluble, and crystalline. Polysaccharides are polymerized monosaccharides, complex, unsweet carbohydrates. Examples are starch, cellulose, and glycogen. They are generally large and often have a complex, branched, connectivity. They are insoluble in water and do not form crystals. Shorter polysaccharides, with 2-15 monomers, are sometimes known as oligosaccharides. ## Lipids Lipids are chiefly fatty acid esters, and are the basic building blocks of biological membranes. Another biological role is energy storage (e.g., triglycerides). Most lipids consist of a polar or hydrophilic head (typically glycerol) and one to three nonpolar or hydrophobic fatty acid tails, and therefore they are amphiphilic. Fatty acids consist of unbranched chains of carbon atoms that are connected by single bonds alone (saturated fatty acids) or by both single and double bonds (unsaturated fatty acids). The chains are usually 14-24 carbon groups long, but it is always an even number. For lipids present in biological membranes, the hydrophilic head is from one of three classes: - Glycolipids, whose heads contain an oligosaccharide with 1-15 saccharide residues. - Phospholipids, whose heads contain a positively charged group that is linked to the tail by a negatively charged phosphate group. - Sterols, whose heads contain a planar steroid ring, for example, cholesterol. Other lipids include prostaglandins and leukotrienes which are both 20-carbon fatty acyl units synthesized from arachidonic acid. They are also known as fatty acids # Hormones Hormones are produced in the endocrine glands, where they are secreted into the bloodstream. They perform a wide range of roles in the various organs including the regulation of metabolic pathways and the regulation of membrane transport processes. Hormones may be grouped into three structural classes: - The steroids are one class of such hormones. They perform a variety of functions, but they are all made from cholesterol. - Simple amines or amino acids. - Peptides or proteins. # Amino acids Amino acids are molecules that contain both amino and carboxylic acid functional groups. (In biochemistry, the term amino acid is used when referring to those amino acids in which the amino and carboxylate functionalities are attached to the same carbon, plus proline which is not actually an amino acid). Amino acids are the building blocks of long polymer chains. With 2-10 amino acids such chains are called peptides, with 10-100 they are often called polypeptides, and longer chains are known as proteins. These protein structures have many structural and functional roles in organisms. There are twenty amino acids that are encoded by the standard genetic code, but there are more than 500 natural amino acids. When amino acids other than the set of twenty are observed in proteins, this is usually the result of modification after translation (protein synthesis). Only two amino acids other than the standard twenty are known to be incorporated into proteins during translation, in certain organisms: - Selenocysteine is incorporated into some proteins at a UGA codon, which is normally a stop codon. - Pyrrolysine is incorporated into some proteins at a UAG codon. For instance, in some methanogens in enzymes that are used to produce methane. Besides those used in protein synthesis, other biologically important amino acids include carnitine (used in lipid transport within a cell), ornithine, GABA and taurine. ## Protein structure The particular series of amino acids that form a protein is known as that protein's primary structure. Proteins have several, well-classified, elements of local structure and these are termed secondary structure. The overall 3D structure of a protein is termed its tertiary structure. Proteins often aggregate into macromolecular structures, or quaternary structure. ### Metalloproteins A metalloprotein is a molecule that contains a metal cofactor. The metal attached to the protein may be an isolated ion or may be a complex organometallic compound or organic compound, such as the porphyrin group found in hemoproteins. In some cases, the metal is coordinated with both a side chain of the protein and an inorganic nonmetallic ion. This type of protein-metal-nonmetal structure is found in iron-sulfur clusters. # Vitamins A vitamin is a compound that cannot be synthesized by a given organism but is nonetheless vital to its survival or health (for example coenzymes). These compounds must be absorbed, or eaten, but typically only in trace quantities. When originally discovered by a Polish doctor, he believed them to all be basic. He therefore named them vital amines. The l was dropped to form the word vitamines. Template:WH Template:WS	https://www.wikidoc.org/index.php/Biomolecular
cb68be008269323102db23717d692fd3f804ca6c	wikidoc	Biosalinity	Biosalinity Biosalinity is the study and practice of using saline (salty) water for irrigating agricultural crops. Many arid and semi-arid areas actually do have sources of water, but the available water is usually brackish (500-5000 ppm salt by weight) or saline (3-5% salt). The water may be present in underground aquifers or as seawater along coastal deserts. With traditional farming practices, saline water results in soil salinization, rendering it unfit for raising most crop plants. Indeed, many arid and semi-arid areas were simply considered unsuitable for agriculture, and agricultural development of these areas was not systematically attempted until the second half of the 20th century. Research in biosalinity includes studies of the biochemical and physiological mechanisms of salt tolerance in plants, breeding and selection for salt tolerance (halotolerance), discovery of periods in a crop plant's life cycle when it may be less sensitive to salt, use of saline irrigation water to increase desirable traits (such as sugar concentration in a fruit) or to control the ripening process, study of the interaction between salinity and soil properties, and development of naturally salt-tolerant plant species (halophytes) into useful agricultural crops. See also halophile bacteria, which thrive under conditions of high salinity. When properly applied (watering well in excess of evapotranspiration, maintaining soil structure for excellent drainage), brackish-water irrigation does not result in increased salinization of the soil. Sometimes this means that farmers have to add extra water after a rainstorm, to carry salts back down to below the root zone.	Biosalinity Biosalinity is the study and practice of using saline (salty) water for irrigating agricultural crops. Many arid and semi-arid areas actually do have sources of water, but the available water is usually brackish (500-5000 ppm salt by weight) or saline (3-5% salt). The water may be present in underground aquifers or as seawater along coastal deserts. With traditional farming practices, saline water results in soil salinization, rendering it unfit for raising most crop plants. Indeed, many arid and semi-arid areas were simply considered unsuitable for agriculture, and agricultural development of these areas was not systematically attempted until the second half of the 20th century. Research in biosalinity includes studies of the biochemical and physiological mechanisms of salt tolerance in plants, breeding and selection for salt tolerance (halotolerance), discovery of periods in a crop plant's life cycle when it may be less sensitive to salt, use of saline irrigation water to increase desirable traits (such as sugar concentration in a fruit) or to control the ripening process, study of the interaction between salinity and soil properties, and development of naturally salt-tolerant plant species (halophytes) into useful agricultural crops. See also halophile bacteria, which thrive under conditions of high salinity. When properly applied (watering well in excess of evapotranspiration, maintaining soil structure for excellent drainage), brackish-water irrigation does not result in increased salinization of the soil. Sometimes this means that farmers have to add extra water after a rainstorm, to carry salts back down to below the root zone. # External links ## Organizations involved in biosaline research and development - CGIAR: Consultative Group on International Agricultural Research - ICBA: International Center for Biosaline Agriculture - USDA's George E. Brown Jr. Salinity Laboratory - The Seawater Foundation ## Popular reviews - Glenn, E. P.; Brown, J. J.; O'Leary, J. W. (1998). "Irrigating Crops with Seawater," Scientific American, Vol. 279, no. 8, Aug. 1998, pp. 56-61. Template:WH Template:WS	https://www.wikidoc.org/index.php/Biosalinity
2bd9f5fc9b9e63b978fb32442d8a574d5bc0851a	wikidoc	Bird Cherry	Bird Cherry The Bird Cherry (Prunus padus; syn. Cerasus padus (L., Prunus racemosa Lam.) Delarbre) is a species of cherry, native to northern Europe and northern Asia, growing even north of the Arctic Circle in Norway. It is the type species of the subgenus Padus with flowers in racemes, which are hermaphroditic and pollinated by bees and flies; it is a deciduous small tree or large shrub 8-16 m tall. The English name refers to the berries, which are astringent and bitter, seldomly used in Western Europe (but commonly eaten in Russia and elsewhere), readily eaten by birds, which do not taste astringency as unpleasant. It was used medicinally during the Middle Ages, and the bark, placed at the door, was supposed to ward off the plague. Another name is the Hagberry, and the fruit can be known as Hags. There are two varieties: - European Bird Cherry Prunus padus var. padus. Europe and western Asia. - Asian Bird Cherry Prunus padus var. commutata. Eastern Asia.	Bird Cherry The Bird Cherry (Prunus padus; syn. Cerasus padus (L., Prunus racemosa Lam.) Delarbre) is a species of cherry, native to northern Europe and northern Asia, growing even north of the Arctic Circle in Norway. It is the type species of the subgenus Padus with flowers in racemes, which are hermaphroditic and pollinated by bees and flies; it is a deciduous small tree or large shrub 8-16 m tall. The English name refers to the berries, which are astringent and bitter, seldomly used in Western Europe (but commonly eaten in Russia and elsewhere), readily eaten by birds, which do not taste astringency as unpleasant. It was used medicinally during the Middle Ages, and the bark, placed at the door, was supposed to ward off the plague. Another name is the Hagberry, and the fruit can be known as Hags. There are two varieties: - European Bird Cherry Prunus padus var. padus. Europe and western Asia. - Asian Bird Cherry Prunus padus var. commutata. Eastern Asia. # External links - Bird cherry information and pictures - Tips to identify bird cherry cs:Střemcha hroznovitá da:Almindelig Hæg de:Gewöhnliche Traubenkirsche hsb:Kitkata wišnja it:Prunus padus lt:Paprastoji ieva nl:Gewone vogelkers no:Hegg nn:Hegg pms:Prunus padus fi:Tuomi sv:Hägg uk:Черемха звичайна	https://www.wikidoc.org/index.php/Bird_Cherry
98e0f6a73d96d16745023ea9688f29f0f3ed037f	wikidoc	Bisphenol A	Bisphenol A Bisphenol A, commonly abbreviated as BPA, is an organic compound with two phenol functional groups. It is used to make polycarbonate plastic and epoxy resins, along with other applications. Known to be estrogenic since the mid 1930s, concerns about the use of bisphenol A in consumer products were regularly reported in the news media in 2008 after several governments issued reports questioning its safety, prompting some retailers to remove products containing it from their shelves. A 2010 report from the United States Food and Drug Administration (FDA) raised further concerns regarding exposure of fetuses, infants and young children. In September 2010, Canada became the first country to declare BPA as a toxic substance. In the European Union and Canada, BPA use is banned in baby bottles. # Production World production capacity of this compound was 1 million tonnes in the 1980s, and more than 2.2 million tonnes in 2009. In 2003, U.S. consumption was 856,000 tonnes, 72% of which was used to make polycarbonate plastic and 21% going into epoxy resins. In the US less than 5% of the BPA produced is used in food contact applications. Bisphenol A was first synthesized by the Russian chemist A.P. Dianin in 1891. This compound is synthesized by the condensation of acetone (hence the suffix A in the name) with two equivalents of phenol. The reaction is catalyzed by a strong acid, such as hydrochloric acid (HCl) or a sulfonated polystyrene resin. Industrially, a large excess of phenol is used to ensure full condensation; the product mixture of the cumene process (acetone and phenol) may also be used as starting material: A large number of ketones undergo analogous condensation reactions. Commercial production of BPA requires distillation – either extraction of BPA from many resinous byproducts under high vacuum, or solvent-based extraction using additional phenol followed by distillation. # Use Bisphenol A is used primarily to make plastics, and products containing bisphenol A-based plastics have been in commerce use since 1957. At least 8 billion pounds of BPA are used by manufacturers yearly. It is a key monomer in production of epoxy resins and in the most common form of polycarbonate plastic. The overall reaction to give polycarbonate can be written: Polycarbonate plastic, which is clear and nearly shatter-proof, is used to make a variety of common products including baby and water bottles, sports equipment, medical and dental devices, dental fillings and sealants, eyeglass lenses, CDs and DVDs, and household electronics. BPA is also used in the synthesis of polysulfones and polyether ketones, as an antioxidant in some plasticizers, and as a polymerization inhibitor in PVC. Epoxy resins containing bisphenol A are used as coatings on the inside of almost all food and beverage cans, however, due to BPA health concerns, in Japan epoxy coating was mostly replaced by PET film. Bisphenol A is also a precursor to the flame retardant tetrabromobisphenol A, and was formerly used as a fungicide. Bisphenol A is a preferred color developer in carbonless copy paper and thermal paper, with the most common public exposure coming from some thermal point of sale receipt paper. BPA-based products are also used in foundry castings and for lining water pipes. ## Identification in plastics "In general, plastics that are marked with recycle codes 1, 2, 4, 5, and 6 are very unlikely to contain BPA. Some, but not all, plastics that are marked with recycle codes 3 or 7 may be made with BPA." There are seven classes of plastics used in packaging applications. Type 7 is the catch-all "other" class, and some type 7 plastics, such as polycarbonate (sometimes identified with the letters "PC" near the recycling symbol) and epoxy resins, are made from bisphenol A monomer. Type 3 (PVC) can also contain bisphenol A as an antioxidant in plasticizers. This is particularly true for "flexible PVC", but not true for PVC pipes. # Health effects Bisphenol A is an endocrine disruptor, which can mimic the body's own hormones and may lead to negative health effects. Early development appears to be the period of greatest sensitivity to its effects, and some studies have linked prenatal exposure to later neurological difficulties. Regulatory bodies have determined safety levels for humans, but those safety levels are currently being questioned or under review as a result of new scientific studies. A 2011 study that investigated the number of chemicals to which pregnant women in the U.S. are exposed found BPA in 96% of women. In 2009, The Endocrine Society released a statement expressing concern over current human exposure to BPA. ## Expert panel conclusions In 2007, a consensus statement by 38 experts on bisphenol A concluded that average levels in people are above those that cause harm to many animals in laboratory experiments. However, they noted that while BPA is not persistent in the environment or in humans, biomonitoring surveys indicate that exposure is continuous, which is problematic because acute animal exposure studies are used to estimate daily human exposure to BPA, and no studies that had examined BPA pharmacokinetics in animal models had followed continuous low level exposures. They added that measurement of BPA levels in serum and other body fluids suggests that either BPA intake is much higher than accounted for, or that BPA can bioaccumulate in some conditions such as pregnancy, or both. A 2011 study, the first to examine BPA in a continuous low level exposure throughout the day, did find an increased absorption and accumulation of BPA in the blood of mice. In 2007 it was reported that among government-funded BPA experiments on lab animals and tissues, 153 found adverse effects and 14 did not, whereas all 13 studies funded by chemical corporations reported no harm. The studies indicating harm reported a variety of deleterious effects in rodent offspring exposed in the womb: abnormal weight gain, insulin resistance, prostate cancer, and excessive mammary gland development. A panel convened by the U.S. National Institutes of Health in 2007 determined that there was "some concern" about BPA's effects on fetal and infant brain development and behavior. The concern over the effect of BPA on infants was also heightened by the fact that infants and children are estimated to have the highest daily intake of BPA. A 2008 report by the U.S. National Toxicology Program (NTP) later agreed with the panel, expressing "some concern for effects on the brain, behavior, and prostate gland in fetuses, infants, and children at current human exposures to bisphenol A," and "minimal concern for effects on the mammary gland and an earlier age for puberty for females in fetuses, infants, and children at current human exposures to bisphenol A." The NTP had "negligible concern that exposure of pregnant women to bisphenol A will result in fetal or neonatal mortality, birth defects, or reduced birth weight and growth in their offspring." ## Obesity A 2008 review has concluded that obesity may be increased as a function of BPA exposure, which "merits concern among scientists and public health officials". A 2009 review of available studies has concluded that "perinatal BPA exposure acts to exert persistent effects on body weight and adiposity". Another 2009 review has concluded that "Eliminating exposures to (BPA) and improving nutrition during development offer the potential for reducing obesity and associated diseases". Other reviews have come with similar conclusions. A later study on rats has suggested that perinatal exposure to drinking water containing 1 mg/L of BPA increased adipogenesis in females at weaning. Other study suggested that larger size-for-age was due to a faster growth rate rather than obesity ## Neurological issues A panel convened by the U.S. National Institutes of Health determined that there was "some concern" about BPA's effects on fetal and infant brain development and behavior. A 2008 report by the U.S. National Toxicology Program (NTP) later agreed with the panel, expressing "some concern for effects on the brain". In January 2010 the FDA expressed the same level of concern. A 2007 review has concluded that BPA, like other xenoestrogens, should be considered as a player within the nervous system that can regulate or alter its functions through multiple pathways. A 2007 review has concluded that low doses of BPA during development have persistent effects on brain structure, function and behavior in rats and mice. A 2008 review concluded that low-dose BPA maternal exposure causes long-term consequences at the level of neurobehavioral development in mice. A 2008 review has concluded that neonatal exposure to Bisphenol-A (BPA) can affect sexually dimorphic brain morphology and neuronal adult phenotypes in mice. A 2008 review has concluded that BPA altered long-term potentiation in the hippocampus and even nanomolar dosage could induce significant effects on memory processes. A 2009 review raised concerns about BPA effect on anteroventral periventricular nucleus. A 2008 study by the Yale School of Medicine demonstrated that adverse neurological effects occur in non-human primates regularly exposed to bisphenol A at levels equal to the United States Environmental Protection Agency's (EPA) maximum safe dose of 50 µg/kg/day. This research found a connection between BPA and interference with brain cell connections vital to memory, learning and mood. A 2010 study with rats prenatally exposed to 40 microg/kg bw BPA has concluded that corticosterone and its actions in the brain are sensitive to the programming effects of BPA. ### Disruption of the dopaminergic system A 2005 review concluded that prenatal and neonatal exposure to BPA in mice can potentiate the central dopaminergic systems, resulting in the supersensitivity to the drugs-of-abuse-induced reward effects and hyperlocomotion. A 2008 review has concluded that BPA mimics estrogenic activity and impacts various dopaminergic processes to enhance mesolimbic dopamine activity resulting in hyperactivity, attention deficits, and a heightened sensitivity to drugs of abuse. A 2009 study on rats has concluded that prenatal and neonatal exposure to low-dose BPA causes deficits in development at dorsolateral striatum via altering the function of dopaminergic receptors. Another 2009 study has found associated changes in the dopaminergic system. ## Thyroid function A 2007 review has concluded that bisphenol-A has been shown to bind to thyroid hormone receptor and perhaps have selective effects on its functions. A 2009 review about environmental chemicals and thyroid function, raised concerns about BPA effects on triiodothyronine and concluded that "available evidence suggests that governing agencies need to regulate the use of thyroid-disrupting chemicals, particularly as such uses relate exposures of pregnant women, neonates and small children to the agents". A 2009 review summarized BPA adverse effects on thyroid hormone action. ## Cancer research According to the WHO's INFOSAN, "animal studies have not provided convincing evidence of risk of cancer from BPA exposure." Neither the U.S. Environmental Protection Agency nor the International Agency for Research on Cancer has evaluated bisphenol A for possible carcinogenic activity. A 2010 review at Tufts University Medical School concluded that Bisphenol A may increase cancer risk. ### Breast cancer A 2008 review has concluded that "perinatal exposure to (...) low doses of (..) BPA, alters breast development and increases breast cancer risk". Another 2008 review concluded that "animal experiments and epidemiological data strengthen the hypothesis that fetal exposure to xenoestrogens may be an underlying cause of the increased incidence of breast cancer observed over the last 50 years". A 2009 in vitro study has concluded that BPA is able to induce neoplastic transformation in human breast epithelial cells. Another 2009 study concluded that maternal oral exposure to low concentrations of BPA during lactation increases mammary carcinogenesis in a rodent model. A 2010 study with the mammary glands of the offspring of pregnant rats treated orally with 0, 25 or 250 µg BPA/kg body weight has found that key proteins involved in signaling pathways such as cellular proliferation were regulated at the protein level by BPA. A 2010 study has found that BPA may reduce sensitivity to chemotherapy treatment of specific tumors. ### Neuroblastoma In vitro studies have suggested that BPA can promote the growth of neuroblastoma cells. A 2010 in vitro study has concluded that BPA potently promote invasion and metastasis of neuroblastoma cells through overexpression of MMP-2 and MMP-9 as well as downregulation of TIMP2. ### Prostate development and cancer A 1997 study in mice has found that neonatal BPA exposure of 2 μg/kg increased adult prostate weight. A 2005 study in mice has found that neonatal BPA exposure at 10 μg/kg disrupted the development of the fetal mouse prostate. A 2006 study in rats has shown that neonatal bisphenol A exposure at 10 μg/kg levels increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. A 2007 in vitro study has found that BPA within the range of concentrations currently measured in human serum is associated with permanently increase in prostate size. A 2009 study has found that newborn rats exposed to a low-dose of BPA (10 µg/kg) increased prostate cancer susceptibility when adults. ### DNA methylation Bisphenol A suppresses DNA methylation which is linked to epigenetic changes. ## Reproductive system and sexual behavior research A 2007 study using pregnant mice showed that BPA changes the expression of key developmental genes that form the uterus which may impact female reproductive tract development and the future fertility of female fetuses the mother is carrying. A series of studies made in 2009 found: - Mouse ovary anomalies from exposure as low as 1 µg/kg, concluded that BPA exposure causes long-term adverse reproductive and carcinogenic effects if exposure occurs during prenatal critical periods of differentiation. - Neonatal exposure of as low as 50 µg/kg disrupts ovarian development in mice. - Neonatal BPA exposition of as low as 50 µg/kg permanently alters the hypothalamic estrogen-dependent mechanisms that govern sexual behavior in the adult female rat. - Prenatal exposure to BPA at levels of (10 μg/kg/day) affects behavioral sexual differentiation in male monkeys. - In placental JEG3 cells in vitro BPA may reduce estrogen synthesis. - BPA exposure disrupted the blood-testis barrier when administered to immature, but not to adult, rats. - Exposure to BPA in the workplace was associated with self-reported adult male sexual dysfunction. A 2009 rodent study, funded by EPA and conducted by some of its scientists, concluded that, compared with ethinyl estradiol, low-dose exposures of bisphenol A (BPA) showed no effects on several reproductive functions and behavioral activities measured in female rats. That study was criticized as flawed for using polycarbonate cages in the experiment (since polycarbonate contains BPA) and the claimed resistance of the rats to estradiol, but that claim was contested by the authors and others. Another 2009 rodent study found that BPA exposure during pregnancy has a lasting effect on one of the genes that is responsible for uterine development and subsequent fertility in both mice and humans (HOXA10). The authors concluded, "We don't know what a safe level of BPA is, so pregnant women should avoid BPA exposure." In a 2010 study mice were given BPA at doses thought to be equivalent to levels currently being experienced by humans. The research showed that BPA exposure affects the earliest stages of egg production in the ovaries of the developing mouse fetuses, thus suggesting that the next generation may suffer genetic defects in such biological processes as mitosis and DNA replication. In addition, the research team noted that their study "revealed a striking down-regulation of mitotic/cell cycle genes, raising the possibility that BPA exposure immediately before meiotic entry might act to shorten the reproductive lifespan of the female" by reducing the total pool of fetal oocytes. Another 2010 study with mice concluded that BPA exposure in utero leads to permanent DNA alterations in sensitivity to estrogen. Also in 2010, a rodent study found that by exposing fetal mice to BPA during pregnancy and examining gene expression and DNA in the uteruses of female fetuses, BPA exposure permanently affected the uterus by decreasing regulation of gene expression. The changes caused the mice to over-respond to estrogen throughout adulthood, long after the BPA exposure, thus suggesting that early exposure to BPA genetically "programmed" the uterus to be hyper-responsive to estrogen. Extreme estrogen sensitivity can lead to fertility problems, advanced puberty, altered mammary development and reproductive function, as well as a variety of hormone-related cancers. One of the authors concluded that BPA may be similar to diethylstilbestrol caused birth defects and cancers in young women whose mothers were given the drug during pregnancy. A 2011 study using the rhesus monkey, a species that is very similar to humans in regard to pregnancy and fetal development, found that prenatal exposure to BPA causes changes in female primates' uterus development. A 2011 rodent study found that male rats exposed to BPA had lower sperm counts and testosterone levels than those of unexposed males. A 2011 mice study found that male mice exposed to BPA became demasculinized and behaved more like females in their spatial navigational abilities. They were also less desirable to female mice. ## General research At an Endocrine Society meeting in 2009, new research reported data from animals experimentally treated with BPA. Studies presented at the group's annual meeting show BPA can affect the hearts of women, can permanently damage the DNA of mice, and appear to be entering the human body from a variety of unknown sources. A 2009 in vitro study on cytotrophoblasts cells has found cytoxic effects in exposure of BPA doses from 0.0002 to 0.2 micrograms per millilitre and concluded this finding "suggests that exposure of placental cells to low doses of BPA may cause detrimental effects, leading in vivo to adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction, prematurity and pregnancy loss" A 2009 study in rats concluded that BPA, at the reference safe limit for human exposure, was found to impact intestinal permeability and may represent a risk factor in female offspring for developing severe colonic inflammation in adulthood. A 2010 study on mice has concluded that perinatal exposure to 10 micrograms/mL of BPA in drinking water enhances allergic sensitization and bronchial inflammation and responsiveness in an animal model of asthma,and a 2011 study found that higher BPA concentrations in the urine of the pregnant women at 16 weeks were associated with wheezing, a symptom of asthma, in their babies. ### Studies on humans The first large study of health effects on humans associated with bisphenol A exposure was published in September 2008 by Iain Lang and colleagues in the Journal of the American Medical Association. The cross-sectional study of almost 1,500 people assessed exposure to bisphenol A by looking at levels of the chemical in urine. The authors found that higher bisphenol A levels were significantly associated with heart disease, diabetes, and abnormally high levels of certain liver enzymes. An editorial in the same issue concludes: A later similar study performed by the same group of scientists, published in January 2010, confirmed, despite of lower concentrations of BPA in the second study sample, an associated increased risk for heart disease but not for diabetes or liver enzymes. Patients with the highest levels of BPA in their urine carried a 33% increased risk of coronary heart disease. Studies have associated recurrent miscarriage with BPA serum concentrations, oxidative stress and inflammation in postmenopausal women with urinary concentrations, externalizing behaviors in two-year old children, especially among female children, with mother's urinary concentrations, altered hormone levels in men and declining male sexual function with urinary concentrations. The Canadian Health Measures Survey, 2007 to 2009 published in 2010 found that teenagers carry 30 percent more l bisphenol A (BPA) in their bodies than older adults. The reason for this is not known. A 2010 study that analyzed BPA urinary concentrations has concluded that for people under 18 years of age BPA may negatively impact human immune function. A study done in 2010 reported the daily excretion levels of BPA among European adults in a large-scale and high-quality population-based sample, and it was shown that higher BPA daily excretion was associated with an increase in serum total testosterone concentration in men. A 2011 study found higher BPA levels in women with polycystic ovary syndrome compared to controls. Furthermore, researchers found a statistically significant positive association between male sex hormones and BPA in these women suggesting a potential role of BPA in ovarian dysfunction. A 2010 study found that people over age 18 with higher levels of BPA exposure had higher CMV antibody levels, which suggests their cell-mediated immune system may not be functioning properly. A 2009 study on Chinese workers in BPA factories found that workers were four times more likely to report erectile dysfunction, reduced sexual desire and overall dissatisfaction with their sex life than workers with no heightened BPA exposure. BPA workers were also seven times more likely to have ejaculation difficulties. They were also more likely to report reduced sexual function within one year of beginning employment at the factory, and the higher the exposure, the more likely they were to have sexual difficulties. ### Historical studies The first evidence of the estrogenicity of bisphenol A came from experiments on rats conducted in the 1930s, but it was not until 1997 that adverse effects of low-dose exposure on laboratory animals were first reported. ## Low-dose exposure in animals The current U.S. human exposure limit set by the EPA is 50 µg/kg/day. ## Xenoestrogen There is evidence that bisphenol A functions as a xenoestrogen by binding strongly to estrogen-related receptor γ (ERR-γ). This orphan receptor (endogenous ligand unknown) behaves as a constitutive activator of transcription. BPA seems to bind strongly to ERR-γ (dissociation constant = 5.5 nM), but not to the estrogen receptor (ER). BPA binding to ERR-γ preserves its basal constitutive activity. It can also protect it from deactivation from the selective estrogen receptor modulator 4-hydroxytamoxifen. Different expression of ERR-γ in different parts of the body may account for variations in bisphenol A effects. For instance, ERR-γ has been found in high concentration in the placenta, explaining reports of high bisphenol accumulation in this tissue. # Human exposure sources Bisphenol A has been known to be leached from the plastic lining of canned foods and polycarbonate plastics, especially those that are cleaned with harsh detergents or those which contain acidic or high-temperature liquids. BPA is an ingredient in the internal coating of metal food and beverage cans used to protect the food from direct contact with the can. A recent Health Canada study found that the majority of canned soft drinks it tested had low, but measurable levels of bisphenol A. Furthermore, A study conducted by the University of Texas School of Public Health in 2010, found BPA in 63 of 105 samples of fresh and canned foods, foods sold in plastic packaging, and in cat and dog foods in cans and plastic packaging. This included fresh turkey, canned green beans, and canned infant formula. While most human exposure is through diet, exposure can also occur through air and through skin absorption. A 2011 study published in Environmental Health Perspectives, “Food Packaging and Bisphenol A and Bis(2-Ethyhexyl) Phthalate Exposure: Findings from a Dietary Intervention," selected 20 participants based on their self-reported use of canned and packaged foods to study BPA. Participants ate their usual diets, followed by three days of consuming foods that were not canned or packaged. The study's findings include: 1) evidence of BPA in participants’ urine decreased by 50% to 70% during the period of eating fresh foods; and 2), participants’ reports of their food practices suggested that consumption of canned foods and beverages and restaurant meals were the most likely sources of exposure to BPA in their usual diets. The researchers note that, even beyond these 20 participants, BPA exposure is widespread, with detectable levels in urine samples in more than an estimated 90% of the U.S. population. Free BPA is found in high concentration in thermal paper and carbonless copy paper, which would be expected to be more available for exposure than BPA bound into resin or plastic. Popular uses of thermal paper include receipts, event and cinema tickets, labels, and airline tickets. A Swiss study found that 11 of 13 thermal printing papers contained 8 - 17 g/kg Bisphenol A (BPA). Upon dry finger contact with a thermal paper receipt, roughly 1 μg BPA (0.2 – 6 μg) was transferred to the forefinger and the middle finger. For wet or greasy fingers approximately 10 times more was transferred. Extraction of BPA from the fingers was possible up to 2 hours after exposure. While there is little concern for dermal absorption of BPA, free BPA can readily be transferred to skin and residues on hands can be ingested. Studies conducted by the CDC found bisphenol A in the urine of 95% of adults sampled in 1988–1994 and in 93% of children and adults tested in 2003–04. While the EPA considers exposures up to 50 µg/kg/day to be safe, the most sensitive animal studies show effects at much lower doses. In 2009, a study found that drinking from polycarbonate bottles increased urinary bisphenol A levels by two thirds, from 1.2 micrograms/gram creatinine to 2 micrograms/gram creatinine. Consumer groups recommend that people wishing to lower their exposure to bisphenol A avoid canned food and polycarbonate plastic containers (which shares resin identification code 7 with many other plastics) unless the packaging indicates the plastic is bisphenol A-free. In order to avoid the possibility of BPA leaching into food or drink, the National Toxicology Panel recommends avoiding microwaving food in plastic containers, putting plastics in the dishwasher, or using harsh detergents. In the U.S., consumption of soda, school lunches, and meals prepared outside the home was statistically significantly associated with higher urinary BPA. BPA is also used to form epoxy resin coating of water pipes. In older buildings, such resin coatings are used to avoid replacement of deteriorating hot and cold water pipes. ## Fetal and Early Childhood Exposures Children may be more susceptible to BPA exposure than adults. A recent study found higher urinary concentrations in young children than in adults under typical exposure scenarios. This increased susceptibility is most likely based on their reduced capacity to eliminate xenobiotics and also their estimated higher daily exposure to BPA, adjusted for weight, compared to adults. Infants fed with liquid formula are among the most exposed, and those fed formula from polycarbonate bottles can consume up to 13 micrograms of bisphenol A per kg of body weight per day (μg/kg/day; see table below). In the US and Canada, BPA has been found in infant liquid formula in concentrations varying from 0.48 to 11 ng/g. BPA has been rarely found in infant powder formula (only 1 of 14). While breast milk is the optimal source of nutrition for infants, it is not always an option. The U.S. Department of Health & Human Services (HHS) states that "the benefit of a stable source of good nutrition from infant formula and food outweighs the potential risk of BPA exposure.". A 2010 study of people in Austria, Switzerland, and Germany has suggested polycarbonate (PC) baby bottles as the most prominent role of exposure for infants, and canned food for adults and teenagers. In the United States, the growing concern over BPA exposure in infants in recent years has lead the manufacturers of plastic baby bottles to stop using BPA in their bottles. However, babies may still be exposed if they are fed with old or hand-me-down bottles bought before the companies stopped using BPA. One often overlooked source of exposure occurs when a pregnant woman is exposed, thereby exposing the fetus. Animal studies have shown that BPA can be found in both the placenta and the amniotic fluid of pregnant mice. A small US study in 2009, funded by the EWG, detected an average of 2.8 ng/mL BPA in the blood of 9 out of the 10 umbilical cords tested. After the baby is born, maternal exposure can continue to effect the infant through transfer of BPA to the infant via breast milk. Because of these exposures that can occur both during and after pregnancy, mothers wishing to limit their child’s exposure to BPA should attempt to limit their own exposures during that time period. While the majority of exposures have been shown to come through the diet, accidental ingestion can also be considered a source of exposure. One study conducted in Japan tested plastic baby books to look for possible leaching into saliva when babies chew on them. While the results of this study have yet to be replicated, it gives reason to question whether exposure can also occur in infants through ingestion by chewing on certain books or toys. # Pharmacokinetics There is no agreement between scientists of a physiologically-based pharmacokinetic (PBPK) BPA model for humans. The effects of BPA on an organism depend on how much free BPA is available and for how long cells are exposed to it. Glucuronidation in the liver, by conjugation with glucuronic acid to form the metabolite BPA-glucuronide (BPAG), reduces the amount of free BPA, however BPAG can be deconjugated by beta-glucuronidase, an enzyme present in high concentration in placenta and other tissues. Free BPA can also be inactivated by sulfation, a process that can also be reverted by arylsulfatase C. A 2010 vitro study has shown that placenta P-glycoprotein may efflux BPA from placenta. The best test methods for studying BPA effects are currently under discussion with scientists sharing different opinions. A 2010 review of 80+ biomonitoring studies concluded that the general population is internally exposed to significant amounts of unconjugated BPA (in the ng/ml blood range). Using GC/MS on 20 samples, BPA was detected in 100% of urine samples with a median of 1.25 ng/ml, and 10% of blood samples (LOD 0.5 ng/ml). A 2009 research has found that some drugs, like naproxen, salicylic acid, carbamazepine and mefenamic acid can, in vitro, significantly inhibit BPA glucuronidation. A 2010 study on rats embryos has found that genistein may enhance developmental toxicity of BPA. # Environmental risk In general, studies have shown that BPA can affect growth, reproduction and development in aquatic organisms. Among freshwater organisms, fish appear to be the most sensitive species. Evidence of endocrine-related effects in fish, aquatic invertebrates, amphibians and reptiles has been reported at environmentally relevant exposure levels lower than those required for acute toxicity. There is a widespread variation in reported values for endocrine-related effects, but many fall in the range of 1μg/L to 1 mg/L. BPA can contaminate the environment either directly or through degradation of products containing BPA, such as ocean-borne plastic trash. As an environmental contaminant this compound interferes with nitrogen fixation at the roots of leguminous plants associated with the bacterial symbiont Sinorhizobium meliloti. Despite a half-life in the soil of only 1–10 days, its ubiquity makes it an important pollutant. According to Environment Canada, "initial assessment shows that at low levels, bisphenol A can harm fish and organisms over time. Studies also indicate that it can currently be found in municipal wastewater." A 2009 review of the biological impacts of plasticizers on wildlife published by the Royal Society with a focus on annelids (both aquatic and terrestrial), molluscs, crustaceans, insects, fish and amphibians concluded that BPA have been shown to affect reproduction in all studied animal groups, to impair development in crustaceans and amphibians and to induce genetic aberrations. A large 2010 study of two rivers in Canada found that areas contaminated with hormone-like chemicals including bisphenol A showed females made up 85 per cent of the population of a certain fish, while females made up only 55 per cent in uncontaminated areas. # Government and industry response ## World Health Organization Arguing uncertainty of possible adverse health effects of low dose BPA exposure, especially on the nervous system and on behaviour, and also the differences of exposure of very young children, the WHO announced in November 2009 that it would organize an expert consultation in 2010 to assess BPA safety. The WHO expert panel recommended no new regulations limiting or banning the use of Bisphenol-A; stating that "initiation of public health measures would be premature." ## Australia and New Zealand The Australia and New Zealand Food Safety Authority (Food Standards Australia New Zealand) does not see any health risk with bisphenol A baby bottles if the manufacturer's instructions are followed. Levels of exposure are very low and do not pose a significant health risk. It added that “the move by overseas manufacturers to stop using BPA in baby bottles is a voluntary action and not the result of a specific action by regulators.” It suggests the use of glass baby bottles if parents have any concerns. ## Canada In April 2008, Health Canada concluded that, while adverse health effects were not expected, the margin of safety was too small for formula-fed infants and proposed classifying the chemical as "'toxic' to human health and the environment." After the release of that assessment, Canadian Health Minister Tony Clement announced Canada's intent to ban the import, sale, and advertisement of polycarbonate baby bottles containing bisphenol A due to safety concerns, and investigate ways to reduce BPA contamination of baby formula packaged in metal cans. While the agency concluded that human exposures were less than levels believed to be unsafe, the margin of safety was not high enough for formula-fed infants. Around the same time, Wal-Mart announced that it was immediately ceasing sales in all its Canadian stores of food containers, water and baby bottles, sippy cups, and pacifiers containing bisphenol A, and that it would phase out baby bottles made with it in U.S. stores by early 2009. Nalgene also announced it will stop using the chemical in its products, and Toys-R-Us said it too will cease selling baby bottles made from it. Subsequent news reports showed many retailers removing polycarbonate drinking products from their shelves. The federal government proposed declaring Bisphenol A a hazardous substance in October 2008 and has since placed it on its list of toxic substances. Health officials wrote in Canada Gazette that "It is concluded that bisphenol A be considered as a substance that may be entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health." The federal ministries of health and the environment announced they would seek to restrict imports, sales and advertising of polycarbonate baby bottles containing BPA. In its statement released on 18 October 2008, Health Canada noted that “bisphenol A exposure to newborns and infants is below levels that cause effects” and that the “general public need not be concerned”. Environment Canada listed bisphenol A as a "toxic substance" in September 2010. ## Europe ### European Union The updated 2008 European Union Risk Assessment Report on bisphenol A, published in June 2008, by the European Commission and European Food Safety Authority (EFSA), concluded that bisphenol A-based products, such as polycarbonate plastic and epoxy resins, are safe for consumers and the environment when used as intended. By October 2008, after the Lang Study was published, the EFSA issued a statement concluding that the study provided no grounds to revise the current Tolerable Daily Intake (TDI) level for BPA of 0.05 mg/kg bodyweight. A 2009 scientific study criticized the European risk assessment processes of endocrine disruptors, including BPA. On 22 December 2009, the EU Environment ministers released a statement expressing concerns over recent studies showing adverse effects of exposure to endocrine disruptors. In September 2010, the European Food Safety Authority (EFSA) published its latest scientific opinion, based on a "comprehensive evaluation of recent toxicity data concluded that no new study could be identified, which would call for a revision of the current TDI". The Panel noted that some studies conducted on developing animals have suggested BPA-related effects of possible toxicological relevance, in particular biochemical changes in brain, immune-modulatory effects and enhanced susceptibility to breast tumours but considered that those studies had several shortcomings so the relevance of these findings for human health could not be assessed. On 25 November 2010, the European Union executive commission said it will ban the manufacturing by 1 March 2011 and ban the marketing and market placement of polycarbonate baby bottles containing the organic compound bisphenol A (BPA) by 1 June 2011, according to John Dalli, commissioner in charge of health and consumer policy. This is backed by a majority of EU governments. The ban was called an over-reaction by Richard Sharpe, of the Medical Research Council's Human Reproductive Sciences Unit, who said to be unaware of any convincing evidence justifying the measure and criticized it as being done on political, rather than scientific grounds. ### Denmark In May 2009, the Danish parliament passed a resolution to ban the use of BPA in baby bottles, which has not been enacted by April 2010. In March 2010, a temporary ban was declared by the Health Minister. ### Belgium On March 2010, senator Philippe Mahoux proposed legislation to ban BPA in food contact plastics. ### France On 5 February 2010, the French Food Safety Agency (AFSSA) questioned the previous assessments of the health risks of BPA, especially in regard to behavioral effects observed in rat pups following exposure in utero and during the first months of life. In April 2010, the AFFSA suggested the adoption of better labels for food products containing BPA. On 24 March 2010, French Senate unanimously approved a proposition of law to ban BPA from baby bottles, although the proposition still depends of Assembly approval. ### Germany On 19 September 2008, the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung, BfR) stated that there was no reason to change the current risk assessment for bisphenol A on the basis of the Lang Study. In October 2009, the German environmental organization Bund für Umwelt und Naturschutz Deutschland requested a ban on BPA for children's products, especially pacifiers, and products that make contact with food. In response, some manufacturers voluntarily removed the problematic pacifiers from the market. ### Netherlands On 6 November 2008, the Dutch Food and Consumer Product Safety Authority (VWA) stated in a newsletter that baby bottles made from polycarbonate plastic do not release measurable concentrations of bisphenol A and therefore are safe to use. ### Switzerland In February 2009, the Swiss Federal Office for Public Health, based on reports of other health agencies, stated that the intake of bisphenol A from food represents no risk to the consumer, including newborns and infants. However, in the same statement, it advised for proper use of polycarbonate baby bottles and listed alternatives. ### Sweden By May 2010, the Swedish Chemicals Agency asked for a BPA ban in baby bottles, but the Swedish Food Safety Authority prefers to await the expected European Food Safety Authority's updated review. The Minister of Environment said to wait for the EFSA review but not for too long. From March 2011 it is prohibited to manufacture babybottles containing bisphenol A and from July 2011 will no longer go to buy them in stores. ### UK In December 2009, responding to a letter from a group of seven scientists that urged the UK Government to "adopt a standpoint consistent with the approach taken by other Governments who have ended the use of BPA in food contact products marketed at children", the UK Food Standards Agency reaffirmed, in January 2009, its view that "exposure of UK consumers to BPA from all sources, including food contact materials, was well below levels considered harmful". ## Turkey As of 10 June 2011, Turkey banned the use of BPA in baby bottles and other PC items produced for babies. ## Japan Between 1998 and 2003, the canning industry voluntarily replaced their BPA-containing epoxy resin can liners with BPA-free polyethylene terephthalate (PET) in many of their products. For other products, they switched to a different epoxy lining that yielded much less migration of BPA into food than the previously used resin. In addition, polycarbonate tableware for school lunches was replaced by BPA-free plastics. As a result of these changes, Japanese risk assessors have found that virtually no BPA is detectable in canned foods or drinks, and blood levels of BPA in people have declined dramatically (50% in one study). ## United States ### September 2008 In September, the National Toxicology Program finalized their report on bisphenol A, finding "some concern", mid-point of a five-level scale, that infants were at risk from exposure to the chemical. At that time, the FDA reassured consumers that current limits were safe, but convened an outside panel of experts to review the issue. The Lang study was also released that month, and David Melzer, a co-author of the study, presented the results of the study before the FDA panel. The editorial accompanying the Lang study's publication in JAMA criticized the FDA's assessment of bisphenol A: "A fundamental problem is that the current ADI for BPA is based on experiments conducted in the early 1980s using outdated methods (only very high doses were tested) and insensitive assays. More recent findings from independent scientists were rejected by the FDA, apparently because those investigators did not follow the outdated testing guidelines for environmental chemicals, whereas studies using the outdated, insensitive assays (predominantly involving studies funded by the chemical industry) are given more weight in arriving at the conclusion that BPA is not harmful at current exposure levels." ### March 2009 Sunoco, a producer of gasoline and chemicals, is now refusing to sell the chemical to companies for use in food and water containers for children younger than 3, saying it can't be certain of the compound's safety. Sunoco plans to require its customers to guarantee that the chemical will not be used in children's food products. The six largest US companies which commercialize baby bottles decided to stop using bisphenol A in their products. Suffolk County, New York banned baby beverage containers made with bisphenol A. On 13 March, leaders from the House and Senate proposed legislation to ban bisphenol A. In the same month, Rochelle Tyl, author of two studies used by FDA to assert BPA safety in August 2008, said those studies didn't claim that BPA is safe because they weren't designed to cover all aspects of the chemical's effects. ### May 2009 The first US jurisdictions to pass regulations limiting or banning BPA were Minnesota and Chicago. Minnesota's regulation takes effect in 2010, "manufacturers of ... children's products containing BPA may not sell them in the state after 1 Jan. 2010. The ban extends to all retailers in the state a year later." The products impacted are known as sippy cups and baby bottles. The City of Chicago adopted a similar ban shortly thereafter. Coverage of Chicago's ban in the news showed a relentless opposition by the industry. A Chicago Tribune article noted an up-hill battle while passing legislation, " used FDA’s position on the issue when they tried to block the city’s measure." In May 2009, the Washington Post accused the manufacturers of food and beverage containers and some of their biggest customers of trying to devise a public relations and lobbying strategy to block government BPA bans. Lyndsey Layton, from the Washington Post, criticized the FDA noting that, "Despite more than 100 published studies by government scientists and university laboratories that have raised health concerns about the chemical, the Food and Drug Administration has deemed it safe largely because of two studies, both funded by a chemical industry trade group". ### June 2009 In June 2009, the FDA announced the decision to reconsider the BPA safety levels. Connecticut was the first US state to ban bisphenol A from infant formula and baby food containers, as well from any reusable food or beverage container. ### July 2009 The California Environmental Protection Agency's Developmental and Reproductive Toxicant Identification Committee unanimously voted against placing Bisphenol A on the state's list of chemicals that are believed to cause reproductive harm. The panel, although concerned over the growing scientific research showing BPA's reproductive harm in animals, found that there was insufficient data of the effects in humans. Critics point out that the same panel failed to add second-hand smoke to the list until 2006, and only one chemical was added to the list in the last three years. ### August 2009 On 3 August, Massachusetts' Department of Public Health advised mothers to take certain actions to prevent possible health impact in children. Mothers with children up to two years old were advised to limit exposure by avoiding products that might contain BPA, such as plastic drinking bottles and other plastic materials with recycling codes of 7 or 3. The Milwaukee Journal Sentinel, as part of an ongoing investigative series into BPA and its effects, revealed plans by the Society of the Plastics Industry to execute a major public relations blitz to promote BPA, including plans to attack and discredit those who report or comment negatively on the monomer and its effects. ### September 2009 On 29 September, the U.S. Environmental Protection Agency announced that it is evaluating BPA, and another five chemicals, for action plan development. ### October 2009 On 28 October, the NIH announced $30,000,000 in stimulus grants to study the health effects of BPA. This money is expected to result in many peer-reviewed publications. ### November 2009 The Consumer Reports magazine published an analysis of BPA content in some canned foods and beverages, where in specific cases the content of a single can of food could exceed the current FDA Cumulative Exposure Daily Intake. ### January 2010 On 15 January, the FDA expressed "some concern", the middle level in the scale of concerns, about the potential effects of BPA on the brain, behavior, and prostate gland in fetuses, infants, and young children, and announced it was taking reasonable steps to reduce human exposure to BPA in the food supply. However, the FDA is not recommending that families change the use of infant formula or foods, as it sees the benefit of a stable source of good nutrition as outweighing the potential risk from BPA exposure. On the same date, the U.S. Department of Health & Human Services released information to help parents to reduce children's BPA exposure. ### February 2010 According to The Milwaukee Journal Sentinel, which supports a BPA ban, after lobbyists for the chemical industry met with administration officials, the EPA delayed BPA regulation and did not include the chemical in an action plan released 30 December 2009. Many US states are considering some sort of BPA ban. ### March 2010 On 29 March, the EPA declared BPA a "chemical of concern". ### April 2010 The 2008–2009 Annual Report of the President’s Cancer Panel declared: "because of the long latency period of many cancers, the available evidence argues for a precautionary approach to these diverse chemicals, which include (...) bisphenol A" Meanwhile, as of April 2011, General Mills has announced that it has found a BPA-free alternative can liner that apparently works even with tomatoes, a highly acidic product that has long baffled the industry in terms of finding a suitable substitute. General Mills says that with the next tomato harvest, it will begin using the BPA-free alternative in tomato products sold by its organic foods subsidiary Muir Glen. Thus far, there has been no word on whether General Mills will use BPA-free alternatives on any of its other canned products. ### February 2011 In August 2010, the Maine Board of Environmental Protection voted unanimously to ban the sale of baby bottles and other reusable food and beverage containers made with bisphenol A as of January 2012. In February 2011, the newly elected governor of Maine, Paul LePage, gained national attention when he spoke on a local TV news show saying he hoped to repeal the ban because, "There hasn't been any science that identifies that there is a problem” and added: "The only thing that I've heard is if you take a plastic bottle and put it in the microwave and you heat it up, it gives off a chemical similar to estrogen. So the worst case is some women may have little beards." In April, the Maine legislature passed a bill to ban the use of BPA in baby bottles, sippy cups, and other reusable food and beverage containers, effective January 1, 2012. Governor LePage refused to sign the bill.	Bisphenol A Bisphenol A, commonly abbreviated as BPA, is an organic compound with two phenol functional groups. It is used to make polycarbonate plastic and epoxy resins, along with other applications. Known to be estrogenic since the mid 1930s, concerns about the use of bisphenol A in consumer products were regularly reported in the news media in 2008 after several governments issued reports questioning its safety, prompting some retailers to remove products containing it from their shelves. A 2010 report from the United States Food and Drug Administration (FDA) raised further concerns regarding exposure of fetuses, infants and young children.[1] In September 2010, Canada became the first country to declare BPA as a toxic substance.[2][3] In the European Union and Canada, BPA use is banned in baby bottles.[4] # Production World production capacity of this compound was 1 million tonnes in the 1980s,[5] and more than 2.2 million tonnes in 2009.[6] In 2003, U.S. consumption was 856,000 tonnes, 72% of which was used to make polycarbonate plastic and 21% going into epoxy resins.[7] In the US less than 5% of the BPA produced is used in food contact applications.[8] Bisphenol A was first synthesized by the Russian chemist A.P. Dianin in 1891.[9][10] This compound is synthesized by the condensation of acetone (hence the suffix A in the name)[11] with two equivalents of phenol. The reaction is catalyzed by a strong acid, such as hydrochloric acid (HCl) or a sulfonated polystyrene resin. Industrially, a large excess of phenol is used to ensure full condensation; the product mixture of the cumene process (acetone and phenol) may also be used as starting material:[5] A large number of ketones undergo analogous condensation reactions. Commercial production of BPA requires distillation – either extraction of BPA from many resinous byproducts under high vacuum, or solvent-based extraction using additional phenol followed by distillation.[5] # Use Bisphenol A is used primarily to make plastics, and products containing bisphenol A-based plastics have been in commerce use since 1957.[12] At least 8 billion pounds of BPA are used by manufacturers yearly.[13] It is a key monomer in production of epoxy resins[14][15] and in the most common form of polycarbonate plastic.[5][16][17] The overall reaction to give polycarbonate can be written: Polycarbonate plastic, which is clear and nearly shatter-proof, is used to make a variety of common products including baby and water bottles, sports equipment, medical and dental devices, dental fillings and sealants, eyeglass lenses, CDs and DVDs, and household electronics.[7] BPA is also used in the synthesis of polysulfones and polyether ketones, as an antioxidant in some plasticizers, and as a polymerization inhibitor in PVC. Epoxy resins containing bisphenol A are used as coatings on the inside of almost all food and beverage cans,[18] however, due to BPA health concerns, in Japan epoxy coating was mostly replaced by PET film.[19] Bisphenol A is also a precursor to the flame retardant tetrabromobisphenol A, and was formerly used as a fungicide.[20] Bisphenol A is a preferred color developer in carbonless copy paper and thermal paper,[21] with the most common public exposure coming from some[22] thermal point of sale receipt paper.[23][24] BPA-based products are also used in foundry castings and for lining water pipes.[8] ## Identification in plastics "In general, plastics that are marked with recycle codes 1, 2, 4, 5, and 6 are very unlikely to contain BPA. Some, but not all, plastics that are marked with recycle codes 3 or 7 may be made with BPA."[25] There are seven classes of plastics used in packaging applications. Type 7 is the catch-all "other" class, and some type 7 plastics, such as polycarbonate (sometimes identified with the letters "PC" near the recycling symbol) and epoxy resins, are made from bisphenol A monomer.[5][26] Type 3 (PVC) can also contain bisphenol A as an antioxidant in plasticizers.[5] This is particularly true for "flexible PVC", but not true for PVC pipes. # Health effects Bisphenol A is an endocrine disruptor, which can mimic the body's own hormones and may lead to negative health effects.[27][28][29][30] Early development appears to be the period of greatest sensitivity to its effects,[31] and some studies have linked prenatal exposure to later neurological difficulties. Regulatory bodies have determined safety levels for humans, but those safety levels are currently being questioned or under review as a result of new scientific studies.[32][33] A 2011 study that investigated the number of chemicals to which pregnant women in the U.S. are exposed found BPA in 96% of women.[34] In 2009, The Endocrine Society released a statement expressing concern over current human exposure to BPA.[35] ## Expert panel conclusions In 2007, a consensus statement by 38 experts on bisphenol A concluded that average levels in people are above those that cause harm to many animals in laboratory experiments. However, they noted that while BPA is not persistent in the environment or in humans, biomonitoring surveys indicate that exposure is continuous, which is problematic because acute animal exposure studies are used to estimate daily human exposure to BPA, and no studies that had examined BPA pharmacokinetics in animal models had followed continuous low level exposures. They added that measurement of BPA levels in serum and other body fluids suggests that either BPA intake is much higher than accounted for, or that BPA can bioaccumulate in some conditions such as pregnancy, or both.[36] A 2011 study, the first to examine BPA in a continuous low level exposure throughout the day, did find an increased absorption and accumulation of BPA in the blood of mice.[37] In 2007 it was reported that among government-funded BPA experiments on lab animals and tissues, 153 found adverse effects and 14 did not, whereas all 13 studies funded by chemical corporations reported no harm. The studies indicating harm reported a variety of deleterious effects in rodent offspring exposed in the womb: abnormal weight gain, insulin resistance, prostate cancer, and excessive mammary gland development.[38] A panel convened by the U.S. National Institutes of Health in 2007 determined that there was "some concern" about BPA's effects on fetal and infant brain development and behavior.[7] The concern over the effect of BPA on infants was also heightened by the fact that infants and children are estimated to have the highest daily intake of BPA.[39] A 2008 report by the U.S. National Toxicology Program (NTP) later agreed with the panel, expressing "some concern for effects on the brain, behavior, and prostate gland in fetuses, infants, and children at current human exposures to bisphenol A," and "minimal concern for effects on the mammary gland and an earlier age for puberty for females in fetuses, infants, and children at current human exposures to bisphenol A." The NTP had "negligible concern that exposure of pregnant women to bisphenol A will result in fetal or neonatal mortality, birth defects, or reduced birth weight and growth in their offspring."[40] ## Obesity A 2008 review has concluded that obesity may be increased as a function of BPA exposure, which "merits concern among scientists and public health officials".[41] A 2009 review of available studies has concluded that "perinatal BPA exposure acts to exert persistent effects on body weight and adiposity".[42] Another 2009 review has concluded that "Eliminating exposures to (BPA) and improving nutrition during development offer the potential for reducing obesity and associated diseases".[43] Other reviews have come with similar conclusions.[44][45] A later study on rats has suggested that perinatal exposure to drinking water containing 1 mg/L of BPA increased adipogenesis in females at weaning.[46] Other study suggested that larger size-for-age was due to a faster growth rate rather than obesity[47] ## Neurological issues A panel convened by the U.S. National Institutes of Health determined that there was "some concern" about BPA's effects on fetal and infant brain development and behavior.[7] A 2008 report by the U.S. National Toxicology Program (NTP) later agreed with the panel, expressing "some concern for effects on the brain".[40] In January 2010 the FDA expressed the same level of concern. A 2007 review has concluded that BPA, like other xenoestrogens, should be considered as a player within the nervous system that can regulate or alter its functions through multiple pathways.[48] A 2007 review has concluded that low doses of BPA during development have persistent effects on brain structure, function and behavior in rats and mice.[49] A 2008 review concluded that low-dose BPA maternal exposure causes long-term consequences at the level of neurobehavioral development in mice.[50] A 2008 review has concluded that neonatal exposure to Bisphenol-A (BPA) can affect sexually dimorphic brain morphology and neuronal adult phenotypes in mice.[51] A 2008 review has concluded that BPA altered long-term potentiation in the hippocampus and even nanomolar dosage could induce significant effects on memory processes.[52] A 2009 review raised concerns about BPA effect on anteroventral periventricular nucleus.[53] A 2008 study by the Yale School of Medicine demonstrated that adverse neurological effects occur in non-human primates regularly exposed to bisphenol A at levels equal to the United States Environmental Protection Agency's (EPA) maximum safe dose of 50 µg/kg/day.[54][55] This research found a connection between BPA and interference with brain cell connections vital to memory, learning and mood. A 2010 study with rats prenatally exposed to 40 microg/kg bw BPA has concluded that corticosterone and its actions in the brain are sensitive to the programming effects of BPA.[56] ### Disruption of the dopaminergic system A 2005 review concluded that prenatal and neonatal exposure to BPA in mice can potentiate the central dopaminergic systems, resulting in the supersensitivity to the drugs-of-abuse-induced reward effects and hyperlocomotion.[57] A 2008 review has concluded that BPA mimics estrogenic activity and impacts various dopaminergic processes to enhance mesolimbic dopamine activity resulting in hyperactivity, attention deficits, and a heightened sensitivity to drugs of abuse.[58] A 2009 study on rats has concluded that prenatal and neonatal exposure to low-dose BPA causes deficits in development at dorsolateral striatum via altering the function of dopaminergic receptors.[59] Another 2009 study has found associated changes in the dopaminergic system.[60] ## Thyroid function A 2007 review has concluded that bisphenol-A has been shown to bind to thyroid hormone receptor and perhaps have selective effects on its functions.[61] A 2009 review about environmental chemicals and thyroid function, raised concerns about BPA effects on triiodothyronine and concluded that "available evidence suggests that governing agencies need to regulate the use of thyroid-disrupting chemicals, particularly as such uses relate exposures of pregnant women, neonates and small children to the agents".[62] A 2009 review summarized BPA adverse effects on thyroid hormone action.[63] ## Cancer research According to the WHO's INFOSAN, "animal studies have not provided convincing evidence of risk of cancer from BPA exposure."[64] Neither the U.S. Environmental Protection Agency[65] nor the International Agency for Research on Cancer[66] has evaluated bisphenol A for possible carcinogenic activity. A 2010 review at Tufts University Medical School concluded that Bisphenol A may increase cancer risk.[67] ### Breast cancer A 2008 review has concluded that "perinatal exposure to (...) low doses of (..) BPA, alters breast development and increases breast cancer risk".[68] Another 2008 review concluded that "animal experiments and epidemiological data strengthen the hypothesis that fetal exposure to xenoestrogens may be an underlying cause of the increased incidence of breast cancer observed over the last 50 years".[69] A 2009 in vitro study has concluded that BPA is able to induce neoplastic transformation in human breast epithelial cells.[70] Another 2009 study concluded that maternal oral exposure to low concentrations of BPA during lactation increases mammary carcinogenesis in a rodent model.[71] A 2010 study with the mammary glands of the offspring of pregnant rats treated orally with 0, 25 or 250 µg BPA/kg body weight has found that key proteins involved in signaling pathways such as cellular proliferation were regulated at the protein level by BPA.[72] A 2010 study has found that BPA may reduce sensitivity to chemotherapy treatment of specific tumors.[73] ### Neuroblastoma In vitro studies have suggested that BPA can promote the growth of neuroblastoma cells.[74][75] A 2010 in vitro study has concluded that BPA potently promote invasion and metastasis of neuroblastoma cells through overexpression of MMP-2 and MMP-9 as well as downregulation of TIMP2.[76] ### Prostate development and cancer A 1997 study in mice has found that neonatal BPA exposure of 2 μg/kg increased adult prostate weight.[77] A 2005 study in mice has found that neonatal BPA exposure at 10 μg/kg disrupted the development of the fetal mouse prostate.[78] A 2006 study in rats has shown that neonatal bisphenol A exposure at 10 μg/kg levels increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis.[79] A 2007 in vitro study has found that BPA within the range of concentrations currently measured in human serum is associated with permanently increase in prostate size.[80] A 2009 study has found that newborn rats exposed to a low-dose of BPA (10 µg/kg) increased prostate cancer susceptibility when adults.[81] ### DNA methylation Bisphenol A suppresses DNA methylation[82] which is linked to epigenetic changes.[83] ## Reproductive system and sexual behavior research A 2007 study using pregnant mice showed that BPA changes the expression of key developmental genes that form the uterus which may impact female reproductive tract development and the future fertility of female fetuses the mother is carrying.[84] A series of studies made in 2009 found: - Mouse ovary anomalies from exposure as low as 1 µg/kg, concluded that BPA exposure causes long-term adverse reproductive and carcinogenic effects if exposure occurs during prenatal critical periods of differentiation.[85] - Neonatal exposure of as low as 50 µg/kg disrupts ovarian development in mice.[86][87][88] - Neonatal BPA exposition of as low as 50 µg/kg permanently alters the hypothalamic estrogen-dependent mechanisms that govern sexual behavior in the adult female rat.[89] - Prenatal exposure to BPA at levels of (10 μg/kg/day) affects behavioral sexual differentiation in male monkeys.[90] - In placental JEG3 cells in vitro BPA may reduce estrogen synthesis.[91] - BPA exposure disrupted the blood-testis barrier when administered to immature, but not to adult, rats.[92] - Exposure to BPA in the workplace was associated with self-reported adult male sexual dysfunction.[93] A 2009 rodent study, funded by EPA and conducted by some of its scientists, concluded that, compared with ethinyl estradiol, low-dose exposures of bisphenol A (BPA) showed no effects on several reproductive functions and behavioral activities measured in female rats.[94] That study was criticized as flawed for using polycarbonate cages in the experiment (since polycarbonate contains BPA) and the claimed resistance of the rats to estradiol,[95] but that claim was contested by the authors and others.[96] Another 2009 rodent study found that BPA exposure during pregnancy has a lasting effect on one of the genes that is responsible for uterine development and subsequent fertility in both mice and humans (HOXA10). The authors concluded, "We don't know what a safe level of BPA is, so pregnant women should avoid BPA exposure."[97] In a 2010 study mice were given BPA at doses thought to be equivalent to levels currently being experienced by humans. The research showed that BPA exposure affects the earliest stages of egg production in the ovaries of the developing mouse fetuses, thus suggesting that the next generation may suffer genetic defects in such biological processes as mitosis and DNA replication. In addition, the research team noted that their study "revealed a striking down-regulation of mitotic/cell cycle genes, raising the possibility that BPA exposure immediately before meiotic entry might act to shorten the reproductive lifespan of the female" by reducing the total pool of fetal oocytes.[98] Another 2010 study with mice concluded that BPA exposure in utero leads to permanent DNA alterations in sensitivity to estrogen.[99] Also in 2010, a rodent study found that by exposing fetal mice to BPA during pregnancy and examining gene expression and DNA in the uteruses of female fetuses, BPA exposure permanently affected the uterus by decreasing regulation of gene expression. The changes caused the mice to over-respond to estrogen throughout adulthood, long after the BPA exposure, thus suggesting that early exposure to BPA genetically "programmed" the uterus to be hyper-responsive to estrogen. Extreme estrogen sensitivity can lead to fertility problems, advanced puberty, altered mammary development and reproductive function, as well as a variety of hormone-related cancers. One of the authors concluded that BPA may be similar to diethylstilbestrol caused birth defects and cancers in young women whose mothers were given the drug during pregnancy.[100] A 2011 study using the rhesus monkey, a species that is very similar to humans in regard to pregnancy and fetal development, found that prenatal exposure to BPA causes changes in female primates' uterus development.[101] A 2011 rodent study found that male rats exposed to BPA had lower sperm counts and testosterone levels than those of unexposed males.[102] A 2011 mice study found that male mice exposed to BPA became demasculinized and behaved more like females in their spatial navigational abilities. They were also less desirable to female mice.[103] ## General research At an Endocrine Society meeting in 2009, new research reported data from animals experimentally treated with BPA.[104] Studies presented at the group's annual meeting show BPA can affect the hearts of women, can permanently damage the DNA of mice, and appear to be entering the human body from a variety of unknown sources.[105] A 2009 in vitro study on cytotrophoblasts cells has found cytoxic effects in exposure of BPA doses from 0.0002 to 0.2 micrograms per millilitre and concluded this finding "suggests that exposure of placental cells to low doses of BPA may cause detrimental effects, leading in vivo to adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction, prematurity and pregnancy loss"[106] A 2009 study in rats concluded that BPA, at the reference safe limit for human exposure, was found to impact intestinal permeability and may represent a risk factor in female offspring for developing severe colonic inflammation in adulthood.[107] A 2010 study on mice has concluded that perinatal exposure to 10 micrograms/mL of BPA in drinking water enhances allergic sensitization and bronchial inflammation and responsiveness in an animal model of asthma,[108]and a 2011 study found that higher BPA concentrations in the urine of the pregnant women at 16 weeks were associated with wheezing, a symptom of asthma, in their babies.[109] ### Studies on humans The first large study of health effects on humans associated with bisphenol A exposure was published in September 2008 by Iain Lang and colleagues in the Journal of the American Medical Association.[110][111] The cross-sectional study of almost 1,500 people assessed exposure to bisphenol A by looking at levels of the chemical in urine. The authors found that higher bisphenol A levels were significantly associated with heart disease, diabetes, and abnormally high levels of certain liver enzymes. An editorial in the same issue concludes: A later similar study performed by the same group of scientists, published in January 2010, confirmed, despite of lower concentrations of BPA in the second study sample, an associated increased risk for heart disease but not for diabetes or liver enzymes. Patients with the highest levels of BPA in their urine carried a 33% increased risk of coronary heart disease.[113] Studies have associated recurrent miscarriage with BPA serum concentrations,[114] oxidative stress and inflammation in postmenopausal women with urinary concentrations,[115] externalizing behaviors in two-year old children, especially among female children, with mother's urinary concentrations,[116] altered hormone levels in men[117][118] and declining male sexual function[119] with urinary concentrations. The Canadian Health Measures Survey, 2007 to 2009 published in 2010 found that teenagers carry 30 percent more l bisphenol A (BPA) in their bodies than older adults. The reason for this is not known.[120] A 2010 study that analyzed BPA urinary concentrations has concluded that for people under 18 years of age BPA may negatively impact human immune function.[121] A study done in 2010 reported the daily excretion levels of BPA among European adults in a large-scale and high-quality population-based sample, and it was shown that higher BPA daily excretion was associated with an increase in serum total testosterone concentration in men.[122] A 2011 study found higher BPA levels in women with polycystic ovary syndrome compared to controls. Furthermore, researchers found a statistically significant positive association between male sex hormones and BPA in these women suggesting a potential role of BPA in ovarian dysfunction.[123] A 2010 study found that people over age 18 with higher levels of BPA exposure had higher CMV antibody levels, which suggests their cell-mediated immune system may not be functioning properly.[124] A 2009 study on Chinese workers in BPA factories found that workers were four times more likely to report erectile dysfunction, reduced sexual desire and overall dissatisfaction with their sex life than workers with no heightened BPA exposure.[125] BPA workers were also seven times more likely to have ejaculation difficulties. They were also more likely to report reduced sexual function within one year of beginning employment at the factory, and the higher the exposure, the more likely they were to have sexual difficulties.[126] ### Historical studies The first evidence of the estrogenicity of bisphenol A came from experiments on rats conducted in the 1930s,[127][128] but it was not until 1997 that adverse effects of low-dose exposure on laboratory animals were first reported.[18] ## Low-dose exposure in animals The current U.S. human exposure limit set by the EPA is 50 µg/kg/day.[140] ## Xenoestrogen There is evidence that bisphenol A functions as a xenoestrogen by binding strongly to estrogen-related receptor γ (ERR-γ).[141] This orphan receptor (endogenous ligand unknown) behaves as a constitutive activator of transcription. BPA seems to bind strongly to ERR-γ (dissociation constant = 5.5 nM), but not to the estrogen receptor (ER).[141] BPA binding to ERR-γ preserves its basal constitutive activity.[141] It can also protect it from deactivation from the selective estrogen receptor modulator 4-hydroxytamoxifen.[141] Different expression of ERR-γ in different parts of the body may account for variations in bisphenol A effects. For instance, ERR-γ has been found in high concentration in the placenta, explaining reports of high bisphenol accumulation in this tissue.[142] # Human exposure sources Template:Rquote Bisphenol A has been known to be leached from the plastic lining of canned foods[143] and polycarbonate plastics, especially those that are cleaned with harsh detergents or those which contain acidic or high-temperature liquids. BPA is an ingredient in the internal coating of metal food and beverage cans used to protect the food from direct contact with the can. A recent Health Canada study found that the majority of canned soft drinks it tested had low, but measurable levels of bisphenol A.[144] Furthermore, A study conducted by the University of Texas School of Public Health in 2010, found BPA in 63 of 105 samples of fresh and canned foods, foods sold in plastic packaging, and in cat and dog foods in cans and plastic packaging. This included fresh turkey, canned green beans, and canned infant formula. [145] While most human exposure is through diet, exposure can also occur through air and through skin absorption.[146] A 2011 study published in Environmental Health Perspectives, “Food Packaging and Bisphenol A and Bis(2-Ethyhexyl) Phthalate Exposure: Findings from a Dietary Intervention," selected 20 participants based on their self-reported use of canned and packaged foods to study BPA. Participants ate their usual diets, followed by three days of consuming foods that were not canned or packaged. The study's findings include: 1) evidence of BPA in participants’ urine decreased by 50% to 70% during the period of eating fresh foods; and 2), participants’ reports of their food practices suggested that consumption of canned foods and beverages and restaurant meals were the most likely sources of exposure to BPA in their usual diets. The researchers note that, even beyond these 20 participants, BPA exposure is widespread, with detectable levels in urine samples in more than an estimated 90% of the U.S. population.[147] Free BPA is found in high concentration in thermal paper and carbonless copy paper, which would be expected to be more available for exposure than BPA bound into resin or plastic.[24][148][149] Popular uses of thermal paper include receipts, event and cinema tickets, labels, and airline tickets. A Swiss study found that 11 of 13 thermal printing papers contained 8 - 17 g/kg Bisphenol A (BPA). Upon dry finger contact with a thermal paper receipt, roughly 1 μg BPA (0.2 – 6 μg) was transferred to the forefinger and the middle finger. For wet or greasy fingers approximately 10 times more was transferred. Extraction of BPA from the fingers was possible up to 2 hours after exposure.[150] While there is little concern for dermal absorption of BPA, free BPA can readily be transferred to skin and residues on hands can be ingested.[8] Studies conducted by the CDC found bisphenol A in the urine of 95% of adults sampled in 1988–1994[151] and in 93% of children and adults tested in 2003–04.[152] While the EPA considers exposures up to 50 µg/kg/day to be safe, the most sensitive animal studies show effects at much lower doses.[129][153] In 2009, a study found that drinking from polycarbonate bottles increased urinary bisphenol A levels by two thirds, from 1.2 micrograms/gram creatinine to 2 micrograms/gram creatinine.[154] Consumer groups recommend that people wishing to lower their exposure to bisphenol A avoid canned food and polycarbonate plastic containers (which shares resin identification code 7 with many other plastics) unless the packaging indicates the plastic is bisphenol A-free.[155] In order to avoid the possibility of BPA leaching into food or drink, the National Toxicology Panel recommends avoiding microwaving food in plastic containers, putting plastics in the dishwasher, or using harsh detergents.[156] In the U.S., consumption of soda, school lunches, and meals prepared outside the home was statistically significantly associated with higher urinary BPA.[157] BPA is also used to form epoxy resin coating of water pipes. In older buildings, such resin coatings are used to avoid replacement of deteriorating hot and cold water pipes.[158] ## Fetal and Early Childhood Exposures Children may be more susceptible to BPA exposure than adults. A recent study found higher urinary concentrations in young children than in adults under typical exposure scenarios.[159] This increased susceptibility is most likely based on their reduced capacity to eliminate xenobiotics[160] and also their estimated higher daily exposure to BPA, adjusted for weight, compared to adults.[161] Infants fed with liquid formula are among the most exposed, and those fed formula from polycarbonate bottles can consume up to 13 micrograms of bisphenol A per kg of body weight per day (μg/kg/day; see table below).[162] In the US and Canada, BPA has been found in infant liquid formula in concentrations varying from 0.48 to 11 ng/g.[163][164] BPA has been rarely found in infant powder formula (only 1 of 14).[163] While breast milk is the optimal source of nutrition for infants, it is not always an option. The U.S. Department of Health & Human Services (HHS) states that "the benefit of a stable source of good nutrition from infant formula and food outweighs the potential risk of BPA exposure.".[165] A 2010 study of people in Austria, Switzerland, and Germany has suggested polycarbonate (PC) baby bottles as the most prominent role of exposure for infants, and canned food for adults and teenagers.[166] In the United States, the growing concern over BPA exposure in infants in recent years has lead the manufacturers of plastic baby bottles to stop using BPA in their bottles. However, babies may still be exposed if they are fed with old or hand-me-down bottles bought before the companies stopped using BPA. One often overlooked source of exposure occurs when a pregnant woman is exposed, thereby exposing the fetus. Animal studies have shown that BPA can be found in both the placenta and the amniotic fluid of pregnant mice. [167] A small US study in 2009, funded by the EWG, detected an average of 2.8 ng/mL BPA in the blood of 9 out of the 10 umbilical cords tested.[168] After the baby is born, maternal exposure can continue to effect the infant through transfer of BPA to the infant via breast milk. [169][170] Because of these exposures that can occur both during and after pregnancy, mothers wishing to limit their child’s exposure to BPA should attempt to limit their own exposures during that time period. While the majority of exposures have been shown to come through the diet, accidental ingestion can also be considered a source of exposure. One study conducted in Japan tested plastic baby books to look for possible leaching into saliva when babies chew on them. [171] While the results of this study have yet to be replicated, it gives reason to question whether exposure can also occur in infants through ingestion by chewing on certain books or toys. # Pharmacokinetics There is no agreement between scientists of a physiologically-based pharmacokinetic (PBPK) BPA model for humans. The effects of BPA on an organism depend on how much free BPA is available and for how long cells are exposed to it. Glucuronidation in the liver, by conjugation with glucuronic acid to form the metabolite BPA-glucuronide (BPAG),[8] reduces the amount of free BPA, however BPAG can be deconjugated by beta-glucuronidase, an enzyme present in high concentration in placenta and other tissues.[172][173] Free BPA can also be inactivated by sulfation, a process that can also be reverted by arylsulfatase C.[172] A 2010 vitro study has shown that placenta P-glycoprotein may efflux BPA from placenta.[174] The best test methods for studying BPA effects are currently under discussion with scientists sharing different opinions.[175] A 2010 review of 80+ biomonitoring studies concluded that the general population is internally exposed to significant amounts of unconjugated BPA (in the ng/ml blood range).[176] Using GC/MS on 20 samples, BPA was detected in 100% of urine samples with a median of 1.25 ng/ml, and 10% of blood samples (LOD 0.5 ng/ml).[177] A 2009 research has found that some drugs, like naproxen, salicylic acid, carbamazepine and mefenamic acid can, in vitro, significantly inhibit BPA glucuronidation.[178] A 2010 study on rats embryos has found that genistein may enhance developmental toxicity of BPA.[179] # Environmental risk In general, studies have shown that BPA can affect growth, reproduction and development in aquatic organisms. Among freshwater organisms, fish appear to be the most sensitive species. Evidence of endocrine-related effects in fish, aquatic invertebrates, amphibians and reptiles has been reported at environmentally relevant exposure levels lower than those required for acute toxicity. There is a widespread variation in reported values for endocrine-related effects, but many fall in the range of 1μg/L to 1 mg/L.[8] BPA can contaminate the environment either directly or through degradation of products containing BPA, such as ocean-borne plastic trash.[180] As an environmental contaminant this compound interferes with nitrogen fixation at the roots of leguminous plants associated with the bacterial symbiont Sinorhizobium meliloti. Despite a half-life in the soil of only 1–10 days, its ubiquity makes it an important pollutant.[181] According to Environment Canada, "initial assessment shows that at low levels, bisphenol A can harm fish and organisms over time. Studies also indicate that it can currently be found in municipal wastewater."[182] A 2009 review of the biological impacts of plasticizers on wildlife published by the Royal Society with a focus on annelids (both aquatic and terrestrial), molluscs, crustaceans, insects, fish and amphibians concluded that BPA have been shown to affect reproduction in all studied animal groups, to impair development in crustaceans and amphibians and to induce genetic aberrations.[183] A large 2010 study of two rivers in Canada found that areas contaminated with hormone-like chemicals including bisphenol A showed females made up 85 per cent of the population of a certain fish, while females made up only 55 per cent in uncontaminated areas.[184] # Government and industry response ## World Health Organization Arguing uncertainty of possible adverse health effects of low dose BPA exposure, especially on the nervous system and on behaviour, and also the differences of exposure of very young children, the WHO announced in November 2009 that it would organize an expert consultation in 2010 to assess BPA safety.[64] The WHO expert panel recommended no new regulations limiting or banning the use of Bisphenol-A; stating that "initiation of public health measures would be premature."[185] ## Australia and New Zealand The Australia and New Zealand Food Safety Authority (Food Standards Australia New Zealand) does not see any health risk with bisphenol A baby bottles if the manufacturer's instructions are followed. Levels of exposure are very low and do not pose a significant health risk. It added that “the move by overseas manufacturers to stop using BPA in baby bottles is a voluntary action and not the result of a specific action by regulators.”[1] It suggests the use of glass baby bottles if parents have any concerns.[186] ## Canada In April 2008, Health Canada concluded that, while adverse health effects were not expected, the margin of safety was too small for formula-fed infants[187] and proposed classifying the chemical as "'toxic' to human health and the environment."[188] After the release of that assessment, Canadian Health Minister Tony Clement announced Canada's intent to ban the import, sale, and advertisement of polycarbonate baby bottles containing bisphenol A due to safety concerns, and investigate ways to reduce BPA contamination of baby formula packaged in metal cans. While the agency concluded that human exposures were less than levels believed to be unsafe, the margin of safety was not high enough for formula-fed infants.[31][189] Around the same time, Wal-Mart announced that it was immediately ceasing sales in all its Canadian stores of food containers, water and baby bottles, sippy cups, and pacifiers containing bisphenol A, and that it would phase out baby bottles made with it in U.S. stores by early 2009.[190] Nalgene also announced it will stop using the chemical in its products,[191] and Toys-R-Us said it too will cease selling baby bottles made from it.[192] Subsequent news reports showed many retailers removing polycarbonate drinking products from their shelves.[193] The federal government proposed declaring Bisphenol A a hazardous substance in October 2008 and has since placed it on its list of toxic substances. Health officials wrote in Canada Gazette that "It is concluded that bisphenol A be considered as a substance that may be entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health."[194] The federal ministries of health and the environment announced they would seek to restrict imports, sales and advertising of polycarbonate baby bottles containing BPA.[195] In its statement released on 18 October 2008, Health Canada noted that “bisphenol A exposure to newborns and infants is below levels that cause effects” and that the “general public need not be concerned”.[196] Environment Canada listed bisphenol A as a "toxic substance" in September 2010.[197] ## Europe ### European Union The updated 2008 European Union Risk Assessment Report on bisphenol A, published in June 2008, by the European Commission and European Food Safety Authority (EFSA), concluded that bisphenol A-based products, such as polycarbonate plastic and epoxy resins, are safe for consumers and the environment when used as intended.[198] By October 2008, after the Lang Study was published, the EFSA issued a statement concluding that the study provided no grounds to revise the current Tolerable Daily Intake (TDI) level for BPA of 0.05 mg/kg bodyweight.[199] A 2009 scientific study criticized the European risk assessment processes of endocrine disruptors, including BPA.[200] On 22 December 2009, the EU Environment ministers released a statement expressing concerns over recent studies showing adverse effects of exposure to endocrine disruptors.[201] In September 2010, the European Food Safety Authority (EFSA) published its latest scientific opinion, based on a "comprehensive evaluation of recent toxicity data [...] concluded that no new study could be identified, which would call for a revision of the current TDI".[202] The Panel noted that some studies conducted on developing animals have suggested BPA-related effects of possible toxicological relevance, in particular biochemical changes in brain, immune-modulatory effects and enhanced susceptibility to breast tumours but considered that those studies had several shortcomings so the relevance of these findings for human health could not be assessed.[202] On 25 November 2010, the European Union executive commission said it will ban the manufacturing by 1 March 2011 and ban the marketing and market placement of polycarbonate baby bottles containing the organic compound bisphenol A (BPA) by 1 June 2011, according to John Dalli, commissioner in charge of health and consumer policy. This is backed by a majority of EU governments.[4][203] The ban was called an over-reaction by Richard Sharpe, of the Medical Research Council's Human Reproductive Sciences Unit, who said to be unaware of any convincing evidence justifying the measure and criticized it as being done on political, rather than scientific grounds.[204] ### Denmark In May 2009, the Danish parliament passed a resolution to ban the use of BPA in baby bottles, which has not been enacted by April 2010. In March 2010, a temporary ban was declared by the Health Minister.[205] ### Belgium On March 2010, senator Philippe Mahoux proposed legislation to ban BPA in food contact plastics.[206] ### France On 5 February 2010, the French Food Safety Agency (AFSSA) questioned the previous assessments of the health risks of BPA, especially in regard to behavioral effects observed in rat pups following exposure in utero and during the first months of life.[207][208] In April 2010, the AFFSA suggested the adoption of better labels for food products containing BPA.[209] On 24 March 2010, French Senate unanimously approved a proposition of law to ban BPA from baby bottles, although the proposition still depends of Assembly approval.[210] ### Germany On 19 September 2008, the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung, BfR) stated that there was no reason to change the current risk assessment for bisphenol A on the basis of the Lang Study.[211] In October 2009, the German environmental organization Bund für Umwelt und Naturschutz Deutschland requested a ban on BPA for children's products, especially pacifiers,[212] and products that make contact with food.[213] In response, some manufacturers voluntarily removed the problematic pacifiers from the market.[214] ### Netherlands On 6 November 2008, the Dutch Food and Consumer Product Safety Authority (VWA) stated in a newsletter that baby bottles made from polycarbonate plastic do not release measurable concentrations of bisphenol A and therefore are safe to use.[215] ### Switzerland In February 2009, the Swiss Federal Office for Public Health, based on reports of other health agencies, stated that the intake of bisphenol A from food represents no risk to the consumer, including newborns and infants. However, in the same statement, it advised for proper use of polycarbonate baby bottles and listed alternatives.[216] ### Sweden By May 2010, the Swedish Chemicals Agency asked for a BPA ban in baby bottles, but the Swedish Food Safety Authority prefers to await the expected European Food Safety Authority's updated review. The Minister of Environment said to wait for the EFSA review but not for too long.[217][218] From March 2011 it is prohibited to manufacture babybottles containing bisphenol A and from July 2011 will no longer go to buy them in stores. ### UK In December 2009, responding to a letter from a group of seven scientists that urged the UK Government to "adopt a standpoint consistent with the approach taken by other Governments who have ended the use of BPA in food contact products marketed at children",[219] the UK Food Standards Agency reaffirmed, in January 2009, its view that "exposure of UK consumers to BPA from all sources, including food contact materials, was well below levels considered harmful".[220] ## Turkey As of 10 June 2011, Turkey banned the use of BPA in baby bottles and other PC items produced for babies.[221] ## Japan Between 1998 and 2003, the canning industry voluntarily replaced their BPA-containing epoxy resin can liners with BPA-free polyethylene terephthalate (PET) in many of their products. For other products, they switched to a different epoxy lining that yielded much less migration of BPA into food than the previously used resin. In addition, polycarbonate tableware for school lunches was replaced by BPA-free plastics. As a result of these changes, Japanese risk assessors have found that virtually no BPA is detectable in canned foods or drinks, and blood levels of BPA in people have declined dramatically (50% in one study).[222] ## United States ### September 2008 In September, the National Toxicology Program finalized their report on bisphenol A, finding "some concern", mid-point of a five-level scale, that infants were at risk from exposure to the chemical.[40] At that time, the FDA reassured consumers that current limits were safe, but convened an outside panel of experts to review the issue. The Lang study was also released that month, and David Melzer, a co-author of the study, presented the results of the study before the FDA panel.[223] The editorial accompanying the Lang study's publication in JAMA criticized the FDA's assessment of bisphenol A: "A fundamental problem is that the current ADI [acceptable daily intake] for BPA is based on experiments conducted in the early 1980s using outdated methods (only very high doses were tested) and insensitive assays. More recent findings from independent scientists were rejected by the FDA, apparently because those investigators did not follow the outdated testing guidelines for environmental chemicals, whereas studies using the outdated, insensitive assays (predominantly involving studies funded by the chemical industry) are given more weight in arriving at the conclusion that BPA is not harmful at current exposure levels."[30] ### March 2009 Sunoco, a producer of gasoline and chemicals, is now refusing to sell the chemical to companies for use in food and water containers for children younger than 3, saying it can't be certain of the compound's safety. Sunoco plans to require its customers to guarantee that the chemical will not be used in children's food products.[224] The six largest US companies which commercialize baby bottles decided to stop using bisphenol A in their products.[225] Suffolk County, New York banned baby beverage containers made with bisphenol A.[226] On 13 March, leaders from the House and Senate proposed legislation to ban bisphenol A.[227] In the same month, Rochelle Tyl, author of two studies used by FDA to assert BPA safety in August 2008, said those studies didn't claim that BPA is safe because they weren't designed to cover all aspects of the chemical's effects.[228] ### May 2009 The first US jurisdictions to pass regulations limiting or banning BPA were Minnesota and Chicago. Minnesota's regulation takes effect in 2010, "manufacturers of ... children's products containing BPA may not sell them in the state after 1 Jan. 2010. The ban extends to all retailers in the state a year later." The products impacted are known as sippy cups and baby bottles.[229] The City of Chicago adopted a similar ban shortly thereafter. Coverage of Chicago's ban in the news showed a relentless opposition by the industry. A Chicago Tribune article noted an up-hill battle while passing legislation, "[industry officials] used FDA’s position on the issue when they tried to block the city’s measure."[230] In May 2009, the Washington Post accused the manufacturers of food and beverage containers and some of their biggest customers of trying to devise a public relations and lobbying strategy to block government BPA bans. Lyndsey Layton, from the Washington Post, criticized the FDA noting that, "Despite more than 100 published studies by government scientists and university laboratories that have raised health concerns about the chemical, the Food and Drug Administration has deemed it safe largely because of two studies, both funded by a chemical industry trade group".[231] ### June 2009 In June 2009, the FDA announced the decision to reconsider the BPA safety levels.[232] Connecticut was the first US state to ban bisphenol A from infant formula and baby food containers, as well from any reusable food or beverage container.[233] ### July 2009 The California Environmental Protection Agency's Developmental and Reproductive Toxicant Identification Committee unanimously voted against placing Bisphenol A on the state's list of chemicals that are believed to cause reproductive harm. The panel, although concerned over the growing scientific research showing BPA's reproductive harm in animals, found that there was insufficient data of the effects in humans.[234] Critics point out that the same panel failed to add second-hand smoke to the list until 2006, and only one chemical was added to the list in the last three years.[235] ### August 2009 On 3 August, Massachusetts' Department of Public Health advised mothers to take certain actions to prevent possible health impact in children. Mothers with children up to two years old were advised to limit exposure by avoiding products that might contain BPA, such as plastic drinking bottles and other plastic materials with recycling codes of 7 or 3.[236] The Milwaukee Journal Sentinel, as part of an ongoing investigative series into BPA and its effects, revealed plans by the Society of the Plastics Industry to execute a major public relations blitz to promote BPA, including plans to attack and discredit those who report or comment negatively on the monomer and its effects.[237][238] ### September 2009 On 29 September, the U.S. Environmental Protection Agency announced that it is evaluating BPA, and another five chemicals, for action plan development.[239] ### October 2009 On 28 October, the NIH announced $30,000,000 in stimulus grants to study the health effects of BPA. This money is expected to result in many peer-reviewed publications.[240] ### November 2009 The Consumer Reports magazine published an analysis of BPA content in some canned foods and beverages, where in specific cases the content of a single can of food could exceed the current FDA Cumulative Exposure Daily Intake.[241][242] ### January 2010 On 15 January, the FDA expressed "some concern", the middle level in the scale of concerns, about the potential effects of BPA on the brain, behavior, and prostate gland in fetuses, infants, and young children, and announced it was taking reasonable steps to reduce human exposure to BPA in the food supply. However, the FDA is not recommending that families change the use of infant formula or foods, as it sees the benefit of a stable source of good nutrition as outweighing the potential risk from BPA exposure.[1] On the same date, the U.S. Department of Health & Human Services released information to help parents to reduce children's BPA exposure.[243] ### February 2010 According to The Milwaukee Journal Sentinel, which supports a BPA ban, after lobbyists for the chemical industry met with administration officials, the EPA delayed BPA regulation and did not include the chemical in an action plan released 30 December 2009.[244][245] Many US states are considering some sort of BPA ban.[246] ### March 2010 On 29 March, the EPA declared BPA a "chemical of concern".[247][248] ### April 2010 The 2008–2009 Annual Report of the President’s Cancer Panel declared: "because of the long latency period of many cancers, the available evidence argues for a precautionary approach to these diverse chemicals, which include (...) bisphenol A"[249] Meanwhile, as of April 2011[update], General Mills has announced that it has found a BPA-free alternative can liner that apparently works even with tomatoes, a highly acidic product that has long baffled the industry in terms of finding a suitable substitute. General Mills says that with the next tomato harvest, it will begin using the BPA-free alternative in tomato products sold by its organic foods subsidiary Muir Glen.[250] Thus far, there has been no word on whether General Mills will use BPA-free alternatives on any of its other canned products. ### February 2011 In August 2010, the Maine Board of Environmental Protection voted unanimously to ban the sale of baby bottles and other reusable food and beverage containers made with bisphenol A as of January 2012.[251] In February 2011, the newly elected governor of Maine, Paul LePage, gained national attention when he spoke on a local TV news show saying he hoped to repeal the ban because, "There hasn't been any science that identifies that there is a problem” and added: "The only thing that I've heard is if you take a plastic bottle and put it in the microwave and you heat it up, it gives off a chemical similar to estrogen. So the worst case is some women may have little beards."[252][253] In April, the Maine legislature passed a bill to ban the use of BPA in baby bottles, sippy cups, and other reusable food and beverage containers, effective January 1, 2012. Governor LePage refused to sign the bill.[254]	https://www.wikidoc.org/index.php/Bisphenol_A
434ebac070e49a3b07d10361d7c97d4c06364716	wikidoc	Black Death	Black Death The Black Death, or the Black Plague, was one of the deadliest pandemics in human history, widely thought to have been caused by a bacterium named Yersinia pestis (Bubonic plague), but recently attributed by some to other diseases. The pandemic is thought to have begun in Central Asia or India and spread to Europe during the 1340s. The total number of deaths worldwide is estimated at 75 million people; approximately 25-50 million of which occurred in Europe. The Black Death is estimated to have killed 30% to 60% of Europe's population. It may have reduced the world's population from an estimated 450 million to between 350 and 375 million in 1400. Bubonic plague is thought to have returned to Europe every generation with varying virulence and mortalities until the 1700s. During this period, more than 100 plague epidemics swept across Europe. On its return in 1603, the plague killed 38,000 Londoners. Other notable 17th century outbreaks were the Italian Plague of 1629-1631, the Great Plague of Seville (1647-1652), the Great Plague of London (1665–1666), the Great Plague of Vienna (1679). There is some controversy over the identity of the disease, but in its virulent form, after the Great Plague of Marseille in 1720–1722, the Great Plague of 1738 (which hit eastern Europe), and the 1771 plague in Moscow, it seems to have disappeared from Europe in the 19th century. The 14th century eruption of the Black Death had a drastic effect on Europe's population, irrevocably changing the social structure. It was a serious blow to the Roman Catholic Church, and resulted in widespread persecution of minorities such as Jews, foreigners, beggars, and lepers. The uncertainty of daily survival created a general mood of morbidity, influencing people to "live for the moment", as illustrated by Giovanni Boccaccio in The Decameron (1353). # The Great Plague Medieval people called the 14th century catastrophe either the "Great Pestilence"' or the "Great Plague". Writers contemporary to the plague referred to the event as the "Great Mortality". The term "Black Death" was introduced for the first time in 1833. It has been popularly thought that the name came from a striking late-stage sign of the disease, in which the sufferer's skin would blacken due to subepidermal hemorrhages (purpura), and the extremities would darken with gangrene (acral necrosis). However, the term is more likely to refer to black in the sense of glum, lugubrious or dreadful. The Black Death was, according to chronicles, characterized by buboes (swellings in lymph nodes), like the late 19th century Asian Bubonic plague. Scientists and historians at the beginning of the 20th century assumed that the Black Death was an outbreak of the same disease, caused by the bacterium Yersinia pestis and spread by fleas with the help of animals like the black rat (Rattus rattus). However, this view has recently been questioned by some scientists and historians. New research suggests Black Death is lying dormant. # Plague migration The plague disease, caused by Yersinia pestis, is enzootic (commonly present) in populations of ground rodents in central Asia, but it is not entirely clear where the 14th century pandemic started. The most popular theory places the first cases in the steppes of Central Asia, although some speculate that it originated around northern India, and others, such as the historian Michael W. Dols, argue that the historical evidence concerning epidemics in the Mediterranean and specifically the Plague of Justinian point to a probability that the Black Death originated in Africa and spread to central Asia, where it then became entrenched among the rodent population. Nevertheless, from central Asia it was carried east and west along the Silk Road, by Mongol armies and traders making use of the opportunities of free passage within the Mongol Empire offered by the Pax Mongolica. It was reportedly first introduced to Europe at the trading city of Caffa in the Crimea in 1347. After a protracted siege, during which the Mongol army under Janibeg was suffering the disease, they catapulted the infected corpses over the city walls to infect the inhabitants. The Genoese traders fled, bringing the plague by ship into Sicily and the south of Europe, whence it spread. Whether or not this hypothesis is accurate, it is clear that several pre-existing conditions such as war, famine, and weather contributed to the severity of the Black Death. In China, the thirteenth century Mongol conquest disrupted farming and trading, and led to widespread famine. The population dropped from approximately 120 to 60 million. The 14th century plague is estimated to have killed 30% of the population of China.. In Europe, the Medieval warm period ended sometime towards the end of the fourteenth century, bringing harsher winters and reduced harvests. In the years 1315 to 1317 a catastrophic famine, known as the Great Famine, struck much of North Western Europe. The famine came about as the result of a large population growth in the previous centuries, with the result that, in the early fourteenth century the population began to exceed the number that could be sustained by productive capacity of the land and farmers. In Northern Europe, new technological innovations such as the heavy plough and the three-field system were not as effective in clearing new fields for harvest as they were in the Mediterranean because the north had poor, clay-like, soil. Food shortages and skyrocketing prices were a fact of life for as much as a century before the plague. Wheat, oats, hay, and consequently livestock, were all in short supply, and their scarcity resulted in hunger and malnutrition. The result was a mounting human vulnerability to disease, due to weakened immune systems. The European economy entered a vicious circle in which hunger and chronic, low-level debilitating disease reduced the productivity of labourers, and so the grain output was reduced, causing grain prices to increase. This situation was worsened when landowners and monarchs like Edward III of England (r. 1327-1377) and Philip VI of France (r. 1328-1350), out of a fear that their comparatively high standard of living would decline, raised the fines and rents of their tenants. Standards of living then fell drastically, diets grew more limited, and Europeans as a whole experienced more health problems. In autumn of 1314, heavy rains began to fall, which led to several years of cold and wet winters. The already weak harvests of the north suffered and the seven-year famine ensued. The Great Famine was the worst in European history, reducing the population by at least ten percent. Records recreated from dendrochronological studies show a hiatus in building construction during the period, as well as a deterioration in climate. This was the economic and social situation in which the predictor of the coming disaster, a typhoid (Infected Water) epidemic, emerged. Many thousands died in populated urban centres, most significantly Ypres. In 1318 a pestilence of unknown origin, sometimes identified as anthrax, targeted the animals of Europe, notably sheep and cattle, further reducing the food supply and income of the peasantry. ## Asian outbreak The scenario that would place the first outbreak in central Asia agrees with the first reports of outbreaks in China in the early 1330s. The plague struck the Chinese province of Hubei in 1334. On the heels of the European epidemic, a more widespread disaster occurred in China during 1353–1354. Chinese accounts of this wave of the disease record a spread to eight distinct areas: Hubei, Jiangxi, Shanxi, Hunan, Guangdong, Guangxi, Henan and Suiyuan, throughout the Mongol and Chinese empires. Historian William McNeill noted that voluminous Chinese records on disease and social disruption survive from this period, but no one has studied these sources in depth. It is probable that the Mongols and merchant caravans inadvertently brought the plague from central Asia to the Middle East and Europe. The plague was reported in the trading cities of Constantinople and Trebizond in 1347. ## European outbreak In October 1347, a fleet of Genoese trading ships fleeing Caffa reached the port of Messina in Sicily. By the time the fleet reached Messina, all the crew members were either infected or dead. It is presumed that the ships also carried infected rats and/or fleas. Some ships were found grounded on shorelines, with no one aboard remaining alive. Looting of these lost ships also helped spread the disease. From there, the plague spread to Genoa and Venice by the turn of 1347–1348. From Italy the disease spread northwest across Europe, striking France, Spain, Portugal and England by June 1348, then turned and spread east through Germany and Scandinavia from 1348 to 1350. It was introduced in Norway in 1349 when a ship landed at Askøy, then proceeded to spread to Bjørgvin (modern Bergen). Finally it spread to north-western Russia in 1351; however, the plague largely spared some parts of Europe, including the Kingdom of Poland and isolated parts of Belgium and The Netherlands. At Siena, Agnolo di Tura wrote: "They died by the hundreds, both day and night, and all were thrown in … ditches and covered with earth. And as soon as those ditches were filled, more were dug. And I, Agnolo di Tura … buried my five children with my own hands … And so many died that all believed it was the end of the world." ## Middle Eastern outbreak The plague struck various countries in the Middle East during the pandemic, leading to serious depopulation and permanent change in both economic and social structures. As it spread to western Europe, the disease also entered the region from southern Russia. By autumn 1347, the plague reached Alexandria in Egypt, probably through the port's trade with Constantinople, and ports on the Black Sea. During 1348, the disease traveled eastward to Gaza, and north along the eastern coast to cities in Lebanon, Syria and Palestine, including Ashkelon, Acre, Jerusalem, Sidon, Damascus, Homs, and Aleppo. In 1348–49, the disease reached Antioch. The city's residents fled to the north, most of them dying during the journey, but the infection had been spread to the people of Asia Minor. Mecca became infected in 1349. During the same year, records show the city of Mawsil (Mosul) suffered a massive epidemic, and the city of Baghdad experienced a second round of the disease. In 1351, Yemen experienced an outbreak of the plague. This coincided with the return of King Mujahid of Yemen from imprisonment in Cairo. His party may have brought the disease with them from Egypt. ## Recurrence In England, in the absence of census figures, historians propose a range of pre-incident population figures from as high as 7 million to as low as 4 million in 1300, and a post-incident population figure as low as 2 million. By the end of 1350 the Black Death had subsided, but it never really died out in England over the next few hundred years: there were further outbreaks in 1361–62, 1369, 1379–83, 1389–93, and throughout the first half of the 15th century. Plague often killed 10% of a community in less than a year - in the worst epidemics, such as at Norwich in 1579 and Newcastle in 1636, as many as 30 or 40%. The most general outbreaks in Tudor and Stuart England, all coinciding with years of plague in Germany and the Low Countries, seem to have begun in 1498, 1535, 1543, 1563, 1589, 1603, 1625 and 1636. The plague repeatedly returned to haunt Europe and the Mediterranean throughout the fourteenth to seventeenth centuries, and although bubonic plague still occurs in isolated cases today, the Great Plague of London in 1665–1666 is generally recognized as one of the last major outbreaks. The plague of 1575–77 claimed some 50,000 victims in Venice. In 1634, an outbreak of plague killed 15,000 Munich residents. Late outbreaks in central Europe include the Italian Plague of 1629-1631, which is associated with troop movements during the Thirty Years' War, and the Great Plague of Vienna in 1679. About 200,000 people in Moscow died of the disease from 1654 to 1656. The last plague outbreak ravaged Oslo in 1654. In 1656 the plague killed about half of Naples's 300,000 inhabitants. Amsterdam was ravaged in 1663–1664, with a mortality given as 50,000. A plague epidemic that followed the Great Northern War (1700-1721, Sweden v. Russia and allies) wiped out almost 1/3 of the population in the region. An estimated one-third of East Prussia's population died in the plague of 1709-1711. The plague of 1710 killed two-thirds of the inhabitants of Helsinki. An outbreak of plague between 1710 and 1711 claimed a third of Stockholm’s population. During the Great Plague of 1738, the epidemic struck again, this time in Eastern Europe, spreading from Ukraine to the Adriatic Sea, then onwards by ship to infect some in Tunisia. The destruction in several Romanian cities such as Timişoara was formidable, claiming tens of thousands of lives. # Causes of bubonic infection ## Bubonic plague theory Plague and the ecology of Yersinia pestis in soil, and in rodent and (possibly and importantly) human ectoparasites are reviewed and summarized by Michel Drancourt in modeling sporadic, limited and large plague outbreaks. Modelling of epizootic plague observed in prairie dogs suggests that occasional reservoirs of infection such as an infectious carcass, rather than "blocked fleas" are a better explanation for the observed epizootic behaviour of the disease in nature. An interesting hypothesis about the epidemiology—the appearance, spread and especially disappearance—of plague from Europe is that the flea-bearing rodent reservoir of disease was eventually succeeded by another species. The black rat (Rattus rattus) was originally introduced from Asia to Europe by trade, but was subsequently displaced and succeeded throughout Europe by the bigger brown rat (Rattus norvegicus). The brown rat was not as prone to transmit the germ-bearing fleas to humans in large die-offs due to a different rat ecology. The dynamic complexities of rat ecology, herd immunity in that reservoir, interaction with human ecology, secondary transmission routes between humans with or without fleas, human herd immunity and changes in each might explain the eruption, dissemination, and re-eruptions of plague that continued for centuries until its (even more) unexplained disappearance. ### Signs and symptoms The three forms of plague brought an array of signs and symptoms to those infected. The septicaemic plague is a form of "blood poisoning," and pneumonic plague is an airborne plague that attacks the lungs before the rest of the body. The classic sign of bubonic plague was the appearance of buboes in the groin, the neck and armpits, which oozed pus and bled. Most victims died within four to seven days after infection. When the plague reached Europe, it first struck port cities and then followed the trade routes, both by sea and land. The bubonic plague was the most commonly seen form during the Black Death, with a mortality rate of thirty to seventy-five percent and symptoms including fever of 38 - 41 °C (101-105 °F), headaches, painful aching joints, nausea and vomiting, and a general feeling of malaise. Of those who contracted the bubonic plague, 4 out of 5 died within eight days. Pneumonic plague was the second most commonly seen form during the Black Death, with a mortality rate of ninety to ninety-five percent. Symptoms included fever, cough and blood-tinged sputum. As the disease progressed, sputum became free flowing and bright red. Septicaemic plague was the least common of the three forms, with a mortality rate close to one hundred percent. Symptoms were high fevers and purple skin patches (purpura due to DIC (Disseminated intravascular coagulation)). David Herlihy identifies another potential sign of the plague: freckle-like spots and rashes. Sources from Viterbo, Italy refer to "the signs which are vulgarly called lenticulae", a word which bears resemblance to the Italian word for freckles, lentiggini. These are not the swellings of buboes, but rather "darkish points or pustules which covered large areas of the body". ## Alternative explanations ### Not bubonic plague? Although Y. pestis as the causitive agent of plague is widely accepted, recent scientific and historical investigations have led some researchers to doubt the long-held belief that the Black Death was an epidemic of bubonic plague. For example, in 2000, Gunnar Karlsson pointed out that the Black Death killed between half and two-thirds of the population of Iceland, although there were no rats in Iceland at this time. Rats were accidentally introduced in the nineteenth century, and have never spread beyond a small number of urban areas attached to seaports. In the fourteenth century there were no urban settlements in Iceland. Iceland was unaffected by the later plagues which are known to have been spread by rats. However, without a rodent reservoir, pneumonic plague can be transmitted from human to human by respiratory transmission, and bubonic and septicemic plague can be transmitted from human to human by human-biting fleas. In addition, it was previously argued that tooth pulp tissue from a fourteenth-century plague cemetery in Montpellier tested positive for molecules associated with Y. pestis. Similar findings were reported in a 2007 study, but other studies have yielded negative results. In September 2003, a team of researchers from Oxford University tested 121 teeth from sixty-six skeletons found in fourteenth-century mass graves. The remains showed no genetic trace of Y. pestis. In 2002, Samuel K. Cohn published the controversial article, “The Black Death: End of the Paradigm.” In the article Cohn argues that the medieval and modern plagues were two distinct diseases differing in their symptoms, signs and epidemiologies. Cohn asserts that the agent causing the bubonic plague, Yersinia pestis, “was first cultured at Hong Kong in 1894.” In turn, the medieval plague that struck Europe, according to Cohn, was not the bubonic plague carried by fleas on rats as traditionally viewed by scientists and historians alike. Cohn’s argument that medieval plague was not rat-based is supported by his claims that the modern and medieval plagues hit in different seasons, had unparalleled cycles of recurrence, and varied in the manner in which immunity was acquired. The modern plague reaches its peak in seasons with high humidity and a temperature of between 50 °F (10 °C) and 78 °F (25.555555555556 °C), as rats’ fleas thrive in this climate. In comparison, the Black Death is recorded as hitting in periods where rats’ fleas could not survive, i.e. hot Mediterranean summers above 78 °F (25.555555555556 °C). In terms of recurrence, the Black Death on average did not resurface in an area for between five and fifteen years after it hit. Contrastingly, modern plagues often hit an affected area yearly for an average of eight to forty years. Last, Cohn presents evidence displaying that individuals gained immunity to the Black Death during the fourteenth century, unlike the modern plague. He states that in 1348 two-thirds of those suffering from plague died in comparison to one-twentieth by 1382. Statistics contrastingly display that immunity to the modern plague has not been acquired. Cohn also points out that in the latter part of the nineteenth century buboes appeared mostly on an infected person's groin, while medieval primary sources indicate that the Black Death caused buboes to appear on necks, armpits, and groins. This difference, he argues, ties in with the fact that fleas caused the modern plague and not the Black Death. Since flea bites do not usually reach beyond a person's ankles, in the modern period the groin was the nearest lymph node that could be infected. As the neck and the armpit were often infected during the medieval plague, it appears less likely that these infections were caused by fleas on rats. In 1984, Graham Twigg published The Black Death: A Biological Reappraisal, where he argued that the climate and ecology of Europe and particularly England made it nearly impossible for rats and fleas to have transmitted bubonic plague. Combining information on the biology of Rattus rattus, Rattus norvegicus, and the common fleas Xenopsylla cheopis and Pulex irritans with modern studies of plague epidemiology, particularly in India, where the R. rattus is a native species and conditions are nearly ideal for plague to be spread, Twigg concludes that it would have been nearly impossible for Yersinia pestis to have been the causative agent of the plague, let alone its explosive spread across Europe. Twigg also shows that the common theory of entirely pneumonic spread does not hold up. He proposes, based on a re-examination of the evidence and symptoms, that the Black Death may actually have been an epidemic of pulmonary anthrax caused by Bacillus anthracis. ### An Ebola-like virus? In 2001, epidemiologists Susan Scott and Christopher Duncan from Liverpool University proposed the theory that the Black Death might have been caused by an Ebola-like virus, not a bacterium. Their rationale was that this plague spread much faster and the incubation period was much longer than other confirmed Y.pestis-caused plagues. A longer period of incubation will allow carriers of the infection to travel farther and infect more people than a shorter one. When the primary vector is humans, as opposed to birds, this is of great importance. Studies of English church records indicate an unusually long incubation period in excess of thirty days, which could account for the rapid spread, topping at 2 miles/day, as this was the average speed a traveler would move across the countryside. The plague also appeared in areas of Europe where rats were uncommon, areas such as Iceland. Epidemiological studies suggest the disease was transferred between humans (which happens rarely with Yersinia pestis and very rarely for Bacillus anthracis), and some genes that determine immunity to Ebola-like viruses are much more widespread in Europe than in other parts of the world. Their research and findings are thoroughly documented in Biology of Plagues. More recently the researchers have published computer modeling demonstrating how the Black Death has made around 10% of Europeans resistant to HIV. ### Anthrax and others? In a similar vein, historian Norman F. Cantor, in his 2001 book In the Wake of the Plague, suggests the Black Death might have been a combination of pandemics including a form of anthrax, a cattle murrain. He cites many forms of evidence including: reported disease symptoms not in keeping with the known effects of either bubonic or pneumonic plague, the discovery of anthrax spores in a plague pit in Scotland, and the fact that meat from infected cattle was known to have been sold in many rural English areas prior to the onset of the plague. It is notable that the means of infection varied widely, from human-to-human contact as in Iceland (rare for plague and cutaneous Bacillus anthracis) to infection in the absence of living or recently dead humans, as in Sicily (which speaks against most viruses). Also, diseases with similar symptoms were generally not distinguished between in that period (see murrain above), at least not in the Christian world; Chinese and Muslim medical records can be expected to yield better information which however only pertains to the specific disease(s) which affected these areas. ### Counter-arguments Historians who believe that the Black Death was indeed caused by bubonic plague have put forth several counterarguments. The uncharacteristically rapid spread of the plague could be due to respiratory droplet transmission, and low levels of immunity in the European population at that period. Historical examples of pandemics of other diseases in populations without previous exposure, such as smallpox and tuberculosis transmitted by aerosol amongst Native Americans, show that the first instance of an epidemic spreads faster and is far more virulent than later instances among the descendants of survivors, for whom natural selection has produced characteristics that are protective against the disease. Michael McCormick, a historian offering the idea that bubonic plague was indeed the source of the Black Death, explains how archaeological research has confirmed that the black or "ship" rat was indeed present in Roman and medieval Europe. Also, the DNA of Y. pestis has been identified in the teeth of the human victims, the same DNA which has been widely believed to have come from the infected rodents. He does not deny the point that there exists a pneumonic expression of Y. pestis transmitted by human-to-human contact, but he states that this does not spread as easily as previous historians have imagined. The rat, according to him, is the only plausible agent of transmission that could have led to such a wide and quick spread of the plague. This is because of rats' proclivity to associate with humans and the ability of their blood to withstand very large concentrations of the bacillus. When rats died, their fleas (which were infected with bacterial blood) found new hosts in the form of humans and animals. The Black Death tapered off in the eighteenth century, and according to McCormick, a rat-based theory of transmission could explain why this occurred. The plague(s) had killed a lot of the human host population of Europe and dwindling cities meant that more people were isolated, and so geography and demography did not allow rats to have as much contact with Europeans. Greatly curtailed communication and transportation systems due to the drastic decline in human population also hindered the replenishment of devastated rat colonies. # CCR5 delta 32 About 10 percent of Europeans have a gene mutation known as CCR5 delta 32 that disables a protein the Human Immunodeficiency Virus (HIV-1) uses to slip into immune system cells. Those with one copy of this gene have some immunity to HIV and those with two copies are virtually immune to the virus. This genetic mutation arose about 700 years ago and it has been suggested by some researchers that survivors of bubonic plague may have selected for the mutation. However, work published in 2003 suggests that smallpox was a more likely driver for the rise of the mutation. # A Malthusian crisis In addition, various historians have adopted yet another theory for the cause of the Black Plague, one that points to social, agricultural, and sometimes economic causes. Often known as the Malthusian limit, scholars use this term to express, and/or explain, certain tragedies throughout history. In his 1798 Essay on the Principle of Population, Thomas Malthus asserted that eventually humans would reproduce so greatly that they would go beyond the limits of food supplies; once they reached this point, some sort of "reckoning" was inevitable. While the Black Death may appear to be a "reckoning" of this sort, it was in fact an external, unpredictable factor and does not therefore fit into the Malthusian theory. In his book, The Black Death and the Transformation of the West, David Herlihy explores this idea of plague as an inevitable crisis wrought on humanity in order to control the population and human resources. In the book The Black Death; A Turning Point in History? (ed. William M. Bowsky) he writes “implies that the Black Death’s pivotal role in late medieval society... was now being challenged. Arguing on the basis of a neo-Malthusian economics, revisionist historians recast the Black Death as a necessary and long overdue corrective to an overpopulated Europe.” Herlihy examines the arguments against the Malthusian crisis, stating “if the Black Death was a response to excessive human numbers it should have arrived several decades earlier” due to the population growth of years before the outbreak of the Black Death. Herlihy also brings up other, biological factors that argue against the plague as a "reckoning" by arguing “the role of famines in affecting population movements is also problematic. The many famines preceding the Black Death, even the ‘great hunger’ of 1314 to 1317, did not result in any appreciable reduction in population levels”. Finally Herlihy concludes the matter stating, “the medieval experience shows us not a Malthusian crisis but a stalemate, in the sense that the community was maintaining at stable levels very large numbers over a lengthy period” and states that the phenomenon should be referred to as more of a deadlock, rather than a crisis, to describe Europe before the epidemics. # Consequences ## Depopulation See also: Medieval demography. Figures for the death toll vary widely by area and from source to source as new research and discoveries come to light. It killed an estimated 75-200 million people in the 14th century. According to medieval historian Philip Daileader in 2007: The trend of recent research is pointing to a figure more like 45% to 50% of the European population dying during a four-year period. There is a fair amount of geographic variation. In Mediterranean Europe and Italy, the South of France and Spain, where plague ran for about four years consecutively, it was probably closer to 80% to 75% of the population. In Germany and England . . . it was probably closer to 20%. ### Asia Estimates of the demographic impact of the plague in Asia are based on both population figures during this time and estimates of the disease's toll on population centers. The initial outbreak of plague in the Chinese province of Hubei in 1334 claimed up to ninety percent of the population, an estimated five million people. During 1353–54, outbreaks in eight distinct areas throughout the Mongol/Chinese empires may have possibly caused the death of two-thirds of China's population, often yielding an estimate of twenty-five million deaths. China had several epidemics and famines from 1200 to 1350s and its population decreased from an estimated 125 million to 65 million in the late 14th century. Japan and Korea had no outbreak of plague. ### Europe and Middle East It is estimated that between one-quarter and one-third of the European population (35 million people) died from the outbreak between 1348 and 1350. Contemporary observers, such as Jean Froissart, estimated the toll to be one-third—less an accurate assessment than an allusion to the Book of Revelation meant to suggest the scope of the plague. Many rural villages were depopulated, mostly the smaller communities, as the few survivors fled to larger towns and cities leaving behind abandoned villages. The Black Death hit the culture of towns and cities disproportionately hard, although rural areas (where most of the population lived) were also significantly affected. A few rural areas, such as Eastern Poland and Lithuania, had such low populations and were so isolated that the plague made little progress. Parts of Hungary and, in modern Belgium, the Brabant region, Hainaut and Limbourg, as well as Santiago de Compostella, were unaffected for unknown reasons (some historians have assumed that the presence of resistant blood groups in the local population helped them resist the disease, although these regions would be touched by the second plague outbreak in 1360–63 and later during the numerous resurgences of the plague). Other areas which escaped the plague were isolated mountainous regions (e.g. the Pyrenees). Larger cities were the worst off, as population densities and close living quarters made disease transmission easier. Cities were also strikingly filthy, infested with lice, fleas and rats, and subject to diseases related to malnutrition and poor hygiene. According to journalist John Kelly, "oefully inadequate sanitation made medieval urban Europe so disease-ridden, no city of any size could maintain its population without a constant influx of immigrants from the countryside".(p. 68) The influx of new citizens facilitated the movement of the plague between communities, and contributed to the longevity of the plague within larger communities. In Italy, Florence's population was reduced from 110,000 or 120,000 inhabitants in 1338 to 50,000 in 1351. Between 60 to 70% of Hamburg and Bremen's population died. In Provence, Dauphiné and Normandy, historians observe a decrease of 60% of fiscal hearths. In some regions, two thirds of the population was annihilated. In the town of Givry, in the Bourgogne region in France, the friar, who used to note 28 to 29 funerals a year, recorded 649 deaths in 1348, half of them in September. About half of Perpignan's population died in several months (only two of the eight physicians survived the plague). England lost 70% of its population, which declined from 7 million before the plague, to 2 million in 1400. All social classes were affected, although the lower classes, living together in unhealthy places, were most vulnerable. Alfonso XI of Castile was the only European monarch to die of the plague, but Peter IV of Aragon lost his wife, his daughter and a niece in six months. Joan of England, daughter of Edward III, died in Bordeaux on her way to Castile to marry Alfonso's son, Pedro. The Byzantine Emperor lost his son, while in the kingdom of France, Joan of Navarre, daughter of Louis X le Hutin and of Margaret of Burgundy, was killed by the plague, as well as Bonne of Luxembourg, the wife of the future John II of France. Furthermore, resurgences of the plague in later years must also be counted: in 1360–62 (the "little mortality"), in 1366–69, 1374–75, 1400, 1407, etc. The plague was not eradicated until the 19th century. The precise demographic impact of the disease in the Middle East is very difficult to calculate. Mortality was particularly high in rural areas, including significant areas of Palestine and Syria. Many surviving rural people fled, leaving their fields and crops, and entire rural provinces are recorded as being totally depopulated. Surviving records in some cities reveal a devastating number of deaths. The 1348 outbreak in Gaza left an estimated 10,000 people dead, while Aleppo recorded a death rate of 500 a day during the same year. In Damascus, at the disease's peak in September and October 1348, a thousand deaths were recorded every day, with overall mortality estimated at between 25 and 38 percent. Syria lost a total of 400,000 people by the time the epidemic subsided in March 1349. In contrast to some higher mortality estimates in Asia and Europe, scholars such as John Fields of Trinity College in Dublin believe the mortality rate in the Middle East was less than one-third of the total population, with higher rates in selected areas. ## Social and economic effects The governments of Europe had no apparent response to the crisis because no one knew its cause or how it spread. In 1348, the plague spread so rapidly that before any physicians or government authorities had time to reflect upon its origins, about a third of the European population had already perished. In crowded cities, it was not uncommon for as much as fifty percent of the population to die. Europeans living in isolated areas suffered less, and monasteries and priests were especially hard hit since they cared for the Black Death's victims. Because fourteenth century healers were at a loss to explain the cause, Europeans turned to astrological forces, earthquakes, and the poisoning of wells by Jews as possible reasons for the plague's emergence. No one in the fourteenth century considered rat control a way to ward off the plague, and people began to believe only God's anger could produce such horrific displays. There were many attacks against Jewish communities. In August of 1349, the Jewish communities of Mainz and Cologne were exterminated. In February of that same year, Christians murdered two thousand Jews in Strasbourg. Where government authorities were concerned, most monarchs instituted measures that prohibited exports of foodstuffs, condemned black market speculators, set price controls on grain, and outlawed large-scale fishing. At best, they proved mostly unenforceable, and at worst they contributed to a continent-wide downward spiral. The hardest hit lands, like England, were unable to buy grain abroad: from France because of the prohibition, and from most of the rest of the grain producers because of crop failures from shortage of labour. Any grain that could be shipped was eventually taken by pirates or looters to be sold on the black market. Meanwhile, many of the largest countries, most notably England and Scotland, had been at war, using up much of their treasury and exacerbating inflation. In 1337, on the eve of the first wave of the Black Death, England and France went to war in what would become known as the Hundred Years' War. Malnutrition, poverty, disease and hunger, coupled with war, growing inflation and other economic concerns made Europe in the mid-fourteenth century ripe for tragedy. The plague did more than just devastate the medieval population; it caused a substantial change in economy and society in all areas of the world. Economic historians like Fernand Braudel have concluded that Black Death exacerbated a recession in the European economy that had been under way since the beginning of the century. As a consequence, social and economic change greatly accelerated during the fourteenth and fifteenth centuries. The church's power was weakened, and in some cases, the social roles it had played were taken over by secular groups. Also the plague led to peasant uprisings in many parts of Europe, such as France (the Jacquerie rebellion), Italy (the Ciompi rebellion, which swept the city of Florence), and in England (the English Peasant Revolt). Europe had been overpopulated before the plague, and a reduction of 30% to 50% of the population could have resulted in higher wages and more available land and food for peasants because of less competition for resources. However, for reasons that are still debated, population levels declined after the Black Death's first outbreak until around 1420 and did not begin to rise again until 1470, so the initial Black Death event on its own does not entirely provide a satisfactory explanation to this extended period of decline in prosperity. See Medieval demography for a more complete treatment of this issue and current theories on why improvements in living standards took longer to evolve. The great population loss brought economic changes based on increased social mobility, as depopulation further eroded the peasants' already weakened obligations to remain on their traditional holdings. In the wake of the drastic population decline brought on by the plague, authorities in Western Europe worked to maintain social order through instituting wage controls. These governmental controls were set in place to ensure that workers received the same salary post-plague as they had before the onslaught of the Black Death. Within England, for example, the Ordinance of Labourers, created in 1349, and the Statute of Labourers, created in 1351, restricted both wage increases and the relocation of workers. If workers attempted to leave their current post, employers were given the right to have them imprisoned. The Statute was strictly enforced in some areas. For example, 7,556 people in the county of Essex were fined for deviating from the Statute in 1352. However, despite examples such as Essex County, the Statute quickly proved to be difficult to enforce due to the scarcity of labour. In Western Europe, the sudden shortage of cheap labour provided an incentive for landlords to compete for peasants with wages and freedoms, an innovation that, some argue, represents the roots of capitalism, and the resulting social upheaval "caused" the Renaissance, and even the Reformation. In many ways the Black Death and its aftermath improved the situation of surviving peasants, notably by the end of the 15th century. In Western Europe, labourers gained more power and were more in demand because of the shortage of labour. In gaining more power, workers following the Black Death often moved away from annual contracts in favour of taking on successive temporary jobs that offered higher wages. Workers such as servants now had the opportunity to leave their current employment to seek better-paying, more attractive positions in areas previously off limits to them. Another positive aspect of the period was that there was more fertile land available to the population; however, the benefits would not be fully realized until 1470, nearly 120 years later, when overall population levels finally began to rise again. In Eastern Europe, by contrast, renewed stringency of laws tied the remaining peasant population more tightly to the land than ever before through serfdom. Sparsely populated Eastern Europe was less affected by the Black Death and so peasant revolts were less common in the fourteenth and fifteenth centuries, not occurring in the east until the sixteenth through nineteenth centuries. Since it is believed to have in part caused the social upheavals of fourteenth- and fifteenth-century Western Europe, some see the Black Death as a factor in the Renaissance and even the Reformation in Western Europe. Therefore, some historians have cited the smaller impact of the plague as a contributing factor in Eastern Europe's failure to experience either of these movements on a similar scale. Extrapolating from this, the Black Death may be seen as partly responsible for Eastern Europe's considerable lag in the move to liberalise government by restricting the power of the monarch and aristocracy. A common example is that by the mid-sixteenth century, England began the process that ultimately ended serfdom there and gave rise to representative government; meanwhile, Russia did not formally abolish serfdom until an autocratic tsar decreed so in 1861. Furthermore, the plague's great population reduction brought cheaper land prices, more food for the average peasant, and a relatively large increase in per capita income among the peasantry, if not immediately, in the coming century. Since the plague left vast areas of farmland untended, they were made available for pasture and put more meat on the market; the consumption of meat and dairy products went up, as did the export of beef and butter from the Low Countries, Scandinavia and northern Germany. However, the upper class often attempted to stop these changes, initially in Western Europe, and more forcefully and successfully in Eastern Europe, by instituting sumptuary laws. These regulated what people (particularly of the peasant class) could wear, so that nobles could ensure that peasants did not begin to dress and act as a higher class member with their increased wealth. Another tactic was to fix prices and wages so that peasants could not demand more with increasing value. This was met with varying success depending on the amount of rebellion it inspired; such a law was one of the causes of the 1381 Peasants' Revolt in England. The increase in social mobility that the Black Death contributed to may have been one means by which the Great Vowel Shift was propagated. ## Persecutions As previously mentioned in reference to the plague's sociocultural impacts, renewed religious fervor and fanaticism bloomed in the wake of the Black Death. Some Christians targeted "various groups such as Jews, friars, foreigners, beggars, pilgrims", lepers and gypsies, thinking that they were to blame for the crisis. Lepers, and other individuals with skin diseases such as acne or psoriasis, were singled out and exterminated throughout Europe. Anyone with leprosy was believed to show an outward sign of a defect of the soul. Differences in cultural and lifestyle practices also led to persecution. Because Jews had a religious obligation to be ritually clean they did not use water from public wells and so were suspected of causing the plague by deliberately poisoning the wells. Typically, comparatively fewer Jews died from the Black Death, in part due to rabbinical laws that promoted habits that were generally cleaner than that of a typical medieval villager. They also were often socially isolated in Jewish ghettos and, as such, were less likely to be infected This led to lower mortality rates in the Jewish population and raised suspicions in people who had no concept of bacterial transmission. Christian mobs attacked Jewish settlements across Europe; by 1351, sixty major and 150 smaller Jewish communities had been destroyed, and more than 350 separate massacres had occurred. This persecution reflected more than ethnic hatred. In many places, attacking Jews was a way to criticize the monarchs who protected them (Jews were under the protection of the king, and often called the "royal treasure"), and monarchic fiscal policies, which were often administered by Jews. An important legacy of the Black Death was to cause the eastward movement of what was left of north European Jewry to Poland and Russia, where it remained until the twentieth century. According to Joseph P. Byrne in his book, The Black Plague, women also faced persecution during the Black Death. Muslim women in Cairo became scapegoats when the plague struck. Byrne writes that in 1438, the sultan of Cairo was informed by his religious lawyers that the arrival of the plague was Allah’s punishment for the sin of fornication and that in accordance with this theory, a law was set in place stating that women were not allowed to make public appearances as they may tempt men into sin. Byrne describes that this law was only lifted when “the wealthy complained that their female servants could not shop for food.” ## Religion The Black Death led to cynicism toward religious officials who could not keep their promises of curing plague victims and banishing the disease. No one, the Church included, was able to cure or accurately explain the reasons for the plague outbreaks. One theory of transmission was that it spread through air, and was referred to as miasma, or 'bad air'. This increased doubt in the clergy's abilities. Extreme alienation with the Church culminated in either support for different religious groups such as the flagellants, which from their late 13th century beginnings grew tremendously during the opening years of the Black Death, and later to a pursuit of pleasure and hedonism. It was a common belief at the time that the plague was due to God's wrath, caused by the sins of mankind; In response, the flagellants travelled from town to town, whipping themselves in an effort to mimic the sufferings of Jesus prior to his crucifixion. Originating in Germany, several miraculous tales emerged from their efforts, such as a child being revived from the dead, and a talking cow. These stories further fuelled the belief that the flagellants were more effective than church leaders. It may have been that the flagellant's later involvement in hedonism was an effort to accelerate or absorb God's wrath, to shorten the time with which others suffered. More likely, the focus of attention and popularity of their cause contributed to a sense that the world itself was ending, and that their individual actions were of no consequence. Sadly, the flagellants may have more likely contributed to the actual spreading of the disease, rather than its cure. Presumably, there were towns that the flagellants visited or passed through which were largely unaffected by the plague until that point, only to be infected by fleas carried either by the flagellant's followers, or the flagellants themselves. This is a common ironic theme in how individuals at the time dealt with the plague -- that in nearly all cases, the methods employed to defend against the plague encouraged its spread. The Black Death hit the monasteries very hard because of their proximity with the sick, who sought refuge there, so that there was a severe shortage of clergy after the epidemic cycle. This resulted in a mass influx of hastily-trained and inexperienced clergy members, many of whom knew little of the discipline and rigor of the veterans they replaced. This led to abuses by the clergy in years afterwards and a further deterioration of the position of the Church in the eyes of the people. ## Other effects After 1350, European culture in general turned very morbid. The general mood was one of pessimism, and contemporary art turned dark with representations of death. In retrospect, it seemed like everything the people thought to do at the time simply made the problem worse. For example, since many equated the plague with God's wrath against sin, and that cats were often considered in league with the Devil, cats were killed en masse. Had this bias toward cats not existed, local rodent populations could have been kept down, lessening the spread of plague-infected fleas from host to host. The practice of alchemy as medicine, previously considered to be normal for most doctors, slowly began to wane as the citizenry began to realize that it seldom affected the progress of the epidemic and that some of the potions and "cures" used by many alchemists only served to worsen the condition of the sick. Liquor, originally made by alchemists, was commonly applied as a remedy for the Black Death, and, as a result, the consumption of liquor in Europe rose dramatically after the plague. The Church often tried to meet the medical need. A plague doctor's duties were often limited to visiting victims to verify whether they had been afflicted or not. Surviving records of contracts drawn up between cities and plague doctors often gave the plague doctor enormous latitude and heavy financial compensation, given the risk of death involved for the plague doctor himself. Most plague doctors were essentially volunteers, as qualified doctors had (usually) already fled, knowing they could do nothing for those affected. Considered an early form of hazmat suit, a plague doctor's clothing consisted of: - A wide-brimmed black hat worn close to the head. At the time, a wide-brimmed black hat would have been identified a person as a doctor, much the same as how nowadays a hat may identify chefs, soldiers, and workers. The wide-brimmed hat may have also been used as partial shielding from infection. - A primitive gas mask in the shape of a bird's beak. A common belief at the time was that the plague was spread by birds. There may have been a belief that by dressing in a bird-like mask, the wearer could draw the plague away from the patient and onto the garment the plague doctor wore. The mask also included red glass eyepieces, which were thought to make the wearer impervious to evil. The beak of the mask was often filled with strongly aromatic herbs and spices to overpower the miasmas or "bad air" which was also thought to carry the plague. At the very least, it may have served a dual purpose of dulling the smell of unburied corpses, sputum, and ruptured bouboules in plague victims. - A long, black overcoat. The overcoat worn by the plague doctor was tucked in behind the beak mask at the neckline to minimize skin exposure. It extended to the feet, and was often coated head to toe in suet or wax. A coating of suet may have been used with the thought that the plague could be drawn away from the flesh of the infected victim and either trapped by the suet, or repelled by the wax. The coating of wax likely served as protection against respiratory droplet contamination, but it was not known at the time if coughing carried the plague. It was likely that the overcoat was waxed to simply prevent sputum or other bodily fluids from clinging to it. - A wooden cane. The cane was used to both direct family members to move the patient, other individuals nearby, and possibly to examine the patient with directly. - Leather breeches. Similar to waders worn by fishermen, leather breeches were worn beneath the cloak to protect the legs and groin from infection. Since the plague often tended to manifest itself first in the lymph nodes, particular attention was paid to protecting the armpits, neck, and groin. The plague doctor's clothing also had a secondary use: to intentionally frighten and warn onlookers. The bedside manner common to doctors of today did not exist at the time; part of the appearance of the plague doctor's clothing was meant to frighten onlookers, and to communicate that something very, very wrong was nearby, and that they too might become infected. It's not known how often or widespread plague doctors were, or how effective they were in treatment of the disease. It's likely that while offering some protection to the wearer, they may have actually contributed more to the spreading of the disease than its treatment, in that the plague doctor unknowingly served as a vector for infected fleas to move from host to host. Although the Black Death highlighted the shortcomings of medical science in the medieval era, it also led to positive changes in the field of medicine. As described by David Herlihy in The Black Death and the Transformation of the West, more emphasis was placed on “anatomical investigations” following the Black Death. How individuals studied the human body notably changed, becoming a process that dealt more directly with the human body in varied states of sickness and health. Further, at this time, the importance of surgeons became more evident. A theory put forth by Stephen O'Brien says the Black Death is likely responsible, through natural selection, for the high frequency of the CCR5-Δ32 genetic defect in people of European descent. The gene affects T cell function and provides protection against HIV, smallpox, and possibly plague, though for the latter, no explanation as to how it would do that exists. This, however, seems unlikely, given that the CCR5-Δ32 gene has been found to be just as common in Bronze Age tissue samples. The Black Death also inspired European architecture to move in two different directions; there was a revival of Greco-Roman styles that, in stone and paint, expressed Petrarch's love of antiquity and a further elaboration of the Gothic style. Late medieval churches had impressive structures centered on verticality, where one's eye is drawn up towards the high ceiling for a religious experience bordering on the mystical. The basic Gothic style was revamped with elaborate decoration in the late medieval period. Sculptors in Italian city-states emulated the work of their Roman forefathers while sculptors in northern Europe, no doubt inspired by the devastation they had witnessed, gave way to a heightened expression of emotion and an emphasis on individual differences. A tough realism came forth in architecture as in literature. Images of intense sorrow, decaying corpses, and individuals with faults as well as virtues emerged. North of the Alps, paintings reached a pinnacle in precise realism with the Flemish school of Jan Van Eyck (c. 1385-1440). The natural world was reproduced in these works with meticulous detail bordering on photography. # Black Death in literature ## Contemporary The Black Death dominated art and literature throughout the generation that experienced it. Much of the most useful manifestations of the Black Death in literature, to historians, comes from the accounts of its chroniclers; contemporary accounts are often the only real way to get a sense of the horror of living through a disaster on such a scale. A few of these chroniclers were famous writers, philosophers and rulers (like Boccaccio and Petrarch). Their writings, however, did not reach the majority of the European population. For example, Petrarch's work was read mainly by wealthy nobles and merchants of Italian city-states. He wrote hundreds of letters and vernacular poetry of great distinction and passed on to later generations a revised interpretation of courtly love. There was, however, one troubadour, writing in the lyric style long out of fashion, who was active in 1348. Peire Lunel de Montech composed the sorrowful sirventes "Meravilhar no·s devo pas las gens" during the height of the plague in Toulouse. Although romances continued to be popular throughout the period, the courtly tradition began to face increasing competition from ordinary writers who became involved in producing gritty realist literature, inspired by their Black Death experiences. This was a new phenomenon, made possible because vernacular education and literature, as well as the study of Latin and classical antiquity, flourished widely, making the written word steadily more accessible during the fourteenth century. For example, Agnolo di Tura, of Siena, records his experience: Father abandoned child, wife husband, one brother another; for this illness seemed to strike through the breath and sight. And so they died. And none could be found to bury the dead for money or friendship. Members of a household brought their dead to a ditch as best they could, without priest, without divine offices ... great pits were dug and piled deep with the multitude of dead. And they died by the hundreds both day and night... And as soon as those ditches were filled more were dug ... And I, Agnolo di Tura, called the Fat, buried my five children with my own hands. And there were also those who were so sparsely covered with earth that the dogs dragged them forth and devoured many bodies throughout the city. There was no one who wept for any death, for all awaited death. And so many died that all believed it was the end of the world. This situation continued until September. The scene Di Tura describes is repeated over and over again all across Europe. In Sicily, Gabriele de'Mussi, a notary, tells of the early spread from Crimea: Alas! our ships enter the port, but of a thousand sailors hardly ten are spared. We reach our homes; our kindred…come from all parts to visit us. Woe to us for we cast at them the darts of death! …Going back to their homes, they in turn soon infected their whole families, who in three days succumbed, and were buried in one common grave. Priests and doctors visiting…from their duties ill, and soon were…dead. O death! cruel, bitter, impious death! …Lamenting our misery, we feared to fly, yet we dared not remain. Henry Knighton tells of the plague’s coming to England: Then the grievous plague came to the sea coasts from Southampton, and came to Bristol, and it was as if all the strength of the town had died, as if they had been hit with sudden death, for there were few who stayed in their beds more than three days, or two days, or even one half a day. Friar John Clyn witnessed its effects in Leinster, after its spread to Ireland in August 1348: That disease entirely stripped vills, cities, castles and towns of inhabitaints of men, so that scarcely anyone would be able to live in them. The plague was so contagious that thous touching the dead or even the sick were immediately infected and died, and the one confessing and the confessor were together led to the grave ... many died from carbuncles and from ulcers and pustles that could be seen on shins and under the armpits; some died, as if in a frenzy, from pain of the head, others from spitting blood ... In the convent of Minors of Drogheda, twenty five, and in Dublin in the same order, twenty three died ... These cities of Dublin and Drogheda were almost destroyed and wasted of inhabitants and men so that in Dublin alone, from the beginning of August right up to Christmas, fourteen thousand men died ... The pestilence gathered strength in Kilkenny during Lent, for between Christmas day and 6 March, eight Friars Preachers died. There was scarcely a house in which only one died but commonly man and wife with their children and family going one way, namely, crossing to death. In addition to these personal accounts, many presentations of the Black Death have entered the general consciousness as great literature. For example, the major works of Boccaccio (The Decameron), Petrarch, Geoffrey Chaucer (The Canterbury Tales), and William Langland (Piers Plowman), which all discuss the Black Death, are generally recognized as some of the best works of their era. La Danse Macabre, or the Dance of death, was a contemporary allegory, expressed as art, drama, and printed work. Its theme was the universality of death, expressing the common wisdom of the time: that no matter one's station in life, the dance of death united all. It consists of the personified Death leading a row of dancing figures from all walks of life to the grave – typically with an emperor, king, pope, monk, youngster, beautiful girl, all in skeleton-state. They were produced under the impact of the Black Death, reminding people of how fragile their lives were and how vain the glories of earthly life. The earliest artistic example is from the frescoed cemetery of the Church of the Holy Innocents in Paris (1424). There are also works by Konrad Witz in Basel (1440), Bernt Notke in Lübeck (1463) and woodcuts by Hans Holbein the Younger (1538). Israil Bercovici claims that the Danse Macabre originated among Sephardic Jews in fourteenth century Spain (Bercovici, 1992, p. 27). The poem "The Rattle Bag" by the Welsh poet Dafydd ap Gwilym (1315-1350 or 1340-1370) has many elements that suggest that it was written as a reflection of the hardships he endured during the Black Death. It also reflects his personal belief that the Black Death was the end of humanity, the Apocalypse, as suggested by his multiple biblical references, particularly the events described in the Book of Revelation. Thomas Nashe also wrote a sonnet about the plague entitled "A Litany in Time of Plague" which was part of Summers last will and Testament (1592). He made countryside visits to remove himself from London in fear of the plague. Additionally see Aleksandr Pushkin's verse play, "Feast in the Time of the Plague". The Black Death quickly entered common folklore in many European countries. In Northern Europe, the plague was personalized as an old, bent woman covered and hooded in black, carrying a broom and a rake. Norwegians told that if she used the rake, some of the population involved might survive, escaping through the teeth of the rake. If she on the other hand used the broom, then the entire population in the area were doomed. The Plague-hag, or Pesta, were vividly drawn by the painter Theodor Kittelsen. Women during and after the Black Death also benefited from the growing importance of vernacular literature because a broader cultural forum became available to them which had previously been restricted to men by the Latin church. And so, they began writing and fostering through patronage the writings and translations of others. For example, in France, Christine de Pizan (1364-1430) became the first woman in Europe to support herself by writing. She wrote in many different literary forms, such as an autobiography and books of moral advice for men and women, as well as poetry on a wide range of topics. In her treatise The Letter to the God of Love, she effectively rebutted Jean de Meun's anti-feminist diatribes found in his conclusion of Romance of the Rose. Her rebuttal is important because it marked the first instance in European history where a woman wrote about the slanders women had long endured. It also led to a debate among de Meun and Pizan sympathizers which lasted until the sixteenth century. ## Modern The Black Plague has been used as a subject or as a setting in modern literature and also media. This may be due to the era's resounding impact on ancient and modern history, and its symbolism and connotations. Albert Camus's novel La Peste deals with the coming of a plague to Algeria. Hermann Hesse's novel Narcissus and Goldmund depicts two monks living during the Black Death, one of whom leaves the monastery to wander around the country, seeing the epidemic's effects firsthand. Norman F. Cantor's novel "In the Wake of the Plague" New York Times Bestseller "Cantor illuminates intricate connections that alter the course of culture, religion, and peace in incalculable ways." - Boston Globe Alessandro Manzoni's novel The Betrothed contains an extraordinary description of the plague that struck Milan in 1630. Although a work of fiction, Manzoni's description of the conditions and events in plague-ravaged Milan are completely historical and extensively documented from primary sources researched by Manzoni. Roger Zelazny's novel Nine Princes in Amber has his protagonist abducted from his birthland and taken to plague-torn England to die. Edgar Allan Poe's short story "The Masque of the Red Death" (1842) is set in an unnamed country during a fictional plague that bears strong resemblance to the Black Death. This possibility is furthered by the climax of the story taking place in a black room. Nobel prizewinner Sigrid Undset's novel Kristin Lavransdatter features the outbreak of the plague in 14th century Norway. Year of Wonders by Geraldine Brooks (2001) is a NY Times and Washington Post Notable Book set in 1666 England. It chronicles the impact of the plague upon the residents of an isolated mountain village, who choose to quarantine themselves rather than contribute to the spread of the disease. Connie Willis's Hugo Award-winning science fiction novel Doomsday Book imagines a future in which historians do field work by travelling into the past as observers. The protagonist, a historian, is sent to the wrong year, arriving in England just as the Black Death is starting. Also, In Michael Crichton's book Timeline, a character is transported through time to a village that is apparently affected by the Black Death. In Kim Stanley Robinson's alternate history novel The Years of Rice and Salt, a Black Death with a virtually 100% mortality rate depopulates Medieval Europe; Western Christendom is utterly destroyed as a civilization and Europe plays no major role in world history. Three novels by Ann Benson play on parallels between the Black Death and emerging diseases in the modern world. In The Plague Tales (1998), Burning Road (2000) and The Physician's Tale (2007), Benson shifts back and forth between the fourteenth century and a world in the near future that has been devastated by an antibiotic-resistant bacterium. She weaves in allusions to many of the contemporary sources, and even modern fiction like Geraldine Brooks' Year of Wonders. Eifelheim by Michael Flynn depicts the interactions between an isolated German village and a group of stranded extraterrestrials as the plague advances (1348-9). Temple of the Winds, the fourth book in the fantasy series The Sword of Truth by Terry Goodkind, centers around a plague that is very similar to the Black Death. Melanie Rawn's fantasy novel, Dragon Prince, shows how a plague-like epidemic affects nobility somewhat less than commoners. It has been alleged (since 1961) that the Black Death inspired one of the most enduring nursery rhymes in the English language, Ring a Ring o' Roses, a pocket full of posies, / Ashes, ashes (or ah-tishoo ah-tishoo), we all fall down. However, there are no written records of the rhyme before the late 19th century and not all of its many variants refer to ashes, sneezing, falling down or anything else that could be connected to the Black Death. The relatively new medium of film has given writers and film producers an opportunity to portray the plague with more visual realism. One of the best known and most expansive depictions of the black plague as art is the movie classic The Seventh Seal, a 1957 film directed by Ingmar Bergman. The knight returns from the Crusades and finds that his home country is ravaged by the Black Death. To his dismay, but not surprise, he discovers that Death has come for him too. The final scene of The Seventh Seal depicts a kind of Danse Macabre. The 1988 science fiction film The Navigator: A Medieval Odyssey portrays a group of 14th-century English villagers who, with the aid of a boy's clairvoyant visions, dig a tunnel to 20th-century New Zealand to escape the Black Death. Panic in the Streets is a black and white, 96-minute film directed by Elia Kazan and released in 1950 by 20th Century Fox. It is film noir semidocumentary shot exclusively on location in New Orleans, Louisiana and featuring numerous New Orleans citizens in speaking and non-speaking roles. The film tells the story of Clinton Reed, an officer of the U.S. Public Health Service (played by Richard Widmark) and a police captain (Paul Douglas) who have only a day or two in which to prevent an epidemic of pneumonic plague after Reed determines a waterfront homicide victim is an index case. It was the film debut of Jack Palance and Zero Mostel. The Black Metal band 1349 is named after the year the Black Death spread through Norway. Danse Macabre by The Faint is a techno dance album alluding to the Black Death. Piers Anthony's 1988 novel, For Love of Evil, is sixth in his Incarnations of Immortality series. In this series, several major forces in mankind's existence are offices held by mortals for various lengths of time before passing to a successor. The Black Death was brought to Europe by Satan to exact revenge on the office of Nature and also discomfited the offices of Death and Fate. Ken Follett's 2007 novel, World Without End, deals with the lives of four children who live through the Black Death from 1327 to 1361. The "Bring out your dead!" scene in the Monty Python movie Monty Python and the Holy Grail famously deals with the ubiquity of plague-related deaths in medieval villages, although the film is explicitly set in 932, and King Arthur would suggest an even earlier date than that. In Garth Nix's book Mister Monday the main characters end up in the Black Death ridden streets. It depicts the roads as covered with piles of the dead. In the beginning of the videogame Neverwinter Nights the player is in a city which suffers from a fictitious, epidemic disease called the "Howling Death", which bears some resemblance to the Black Death.	Black Death The Black Death, or the Black Plague, was one of the deadliest pandemics in human history, widely thought to have been caused by a bacterium named Yersinia pestis (Bubonic plague),[1] but recently attributed by some to other diseases. The pandemic is thought to have begun in Central Asia or India and spread to Europe during the 1340s.[2][3] The total number of deaths worldwide is estimated at 75 million people;[4] approximately 25-50 million of which occurred in Europe.[5][6][7] The Black Death is estimated to have killed 30% to 60% of Europe's population.[8][9][10] It may have reduced the world's population from an estimated 450 million to between 350 and 375 million in 1400.[11] Bubonic plague is thought to have returned to Europe every generation with varying virulence and mortalities until the 1700s.[12] During this period, more than 100 plague epidemics swept across Europe.[13] On its return in 1603, the plague killed 38,000 Londoners.[14] Other notable 17th century outbreaks were the Italian Plague of 1629-1631, the Great Plague of Seville (1647-1652), the Great Plague of London (1665–1666),[15] the Great Plague of Vienna (1679). There is some controversy over the identity of the disease, but in its virulent form, after the Great Plague of Marseille in 1720–1722,[16] the Great Plague of 1738 (which hit eastern Europe), and the 1771 plague in Moscow, it seems to have disappeared from Europe in the 19th century. The 14th century eruption of the Black Death had a drastic effect on Europe's population, irrevocably changing the social structure. It was a serious blow to the Roman Catholic Church, and resulted in widespread persecution of minorities such as Jews, foreigners, beggars, and lepers. The uncertainty of daily survival created a general mood of morbidity, influencing people to "live for the moment", as illustrated by Giovanni Boccaccio in The Decameron (1353). # The Great Plague Medieval people called the 14th century catastrophe either the "Great Pestilence"' or the "Great Plague".[17] Writers contemporary to the plague referred to the event as the "Great Mortality". The term "Black Death" was introduced for the first time in 1833.[18] It has been popularly thought that the name came from a striking late-stage sign of the disease, in which the sufferer's skin would blacken due to subepidermal hemorrhages (purpura), and the extremities would darken with gangrene (acral necrosis). However, the term is more likely to refer to black in the sense of glum, lugubrious or dreadful.[19] The Black Death was, according to chronicles, characterized by buboes (swellings in lymph nodes), like the late 19th century Asian Bubonic plague. Scientists and historians at the beginning of the 20th century assumed that the Black Death was an outbreak of the same disease, caused by the bacterium Yersinia pestis and spread by fleas with the help of animals like the black rat (Rattus rattus). However, this view has recently been questioned by some scientists and historians.[20] New research suggests Black Death is lying dormant.[21] # Plague migration The plague disease, caused by Yersinia pestis, is enzootic (commonly present) in populations of ground rodents in central Asia, but it is not entirely clear where the 14th century pandemic started. The most popular theory places the first cases in the steppes of Central Asia, although some speculate that it originated around northern India, and others, such as the historian Michael W. Dols, argue that the historical evidence concerning epidemics in the Mediterranean and specifically the Plague of Justinian point to a probability that the Black Death originated in Africa and spread to central Asia, where it then became entrenched among the rodent population.[22] Nevertheless, from central Asia it was carried east and west along the Silk Road, by Mongol armies and traders making use of the opportunities of free passage within the Mongol Empire offered by the Pax Mongolica. It was reportedly first introduced to Europe at the trading city of Caffa in the Crimea in 1347. After a protracted siege, during which the Mongol army under Janibeg was suffering the disease, they catapulted the infected corpses over the city walls to infect the inhabitants. The Genoese traders fled, bringing the plague by ship into Sicily and the south of Europe, whence it spread.[23] Whether or not this hypothesis is accurate, it is clear that several pre-existing conditions such as war, famine, and weather contributed to the severity of the Black Death. In China, the thirteenth century Mongol conquest disrupted farming and trading, and led to widespread famine. The population dropped from approximately 120 to 60 million.[24] The 14th century plague is estimated to have killed 30% of the population of China..[25] In Europe, the Medieval warm period ended sometime towards the end of the fourteenth century, bringing harsher winters and reduced harvests. In the years 1315 to 1317 a catastrophic famine, known as the Great Famine, struck much of North Western Europe. The famine came about as the result of a large population growth in the previous centuries, with the result that, in the early fourteenth century the population began to exceed the number that could be sustained by productive capacity of the land and farmers.[26] In Northern Europe, new technological innovations such as the heavy plough and the three-field system were not as effective in clearing new fields for harvest as they were in the Mediterranean because the north had poor, clay-like, soil.[18] Food shortages and skyrocketing prices were a fact of life for as much as a century before the plague. Wheat, oats, hay, and consequently livestock, were all in short supply, and their scarcity resulted in hunger and malnutrition. The result was a mounting human vulnerability to disease, due to weakened immune systems. The European economy entered a vicious circle in which hunger and chronic, low-level debilitating disease reduced the productivity of labourers, and so the grain output was reduced, causing grain prices to increase. This situation was worsened when landowners and monarchs like Edward III of England (r. 1327-1377) and Philip VI of France (r. 1328-1350), out of a fear that their comparatively high standard of living would decline, raised the fines and rents of their tenants.[27] Standards of living then fell drastically, diets grew more limited, and Europeans as a whole experienced more health problems. In autumn of 1314, heavy rains began to fall, which led to several years of cold and wet winters. The already weak harvests of the north suffered and the seven-year famine ensued. The Great Famine was the worst in European history, reducing the population by at least ten percent.[18] Records recreated from dendrochronological studies show a hiatus in building construction during the period, as well as a deterioration in climate.[28] This was the economic and social situation in which the predictor of the coming disaster, a typhoid (Infected Water) epidemic, emerged. Many thousands died in populated urban centres, most significantly Ypres. In 1318 a pestilence of unknown origin, sometimes identified as anthrax, targeted the animals of Europe, notably sheep and cattle, further reducing the food supply and income of the peasantry. ## Asian outbreak The scenario that would place the first outbreak in central Asia agrees with the first reports of outbreaks in China in the early 1330s. The plague struck the Chinese province of Hubei in 1334. On the heels of the European epidemic, a more widespread disaster occurred in China during 1353–1354. Chinese accounts of this wave of the disease record a spread to eight distinct areas: Hubei, Jiangxi, Shanxi, Hunan, Guangdong, Guangxi, Henan and Suiyuan,[29] throughout the Mongol and Chinese empires. Historian William McNeill noted that voluminous Chinese records on disease and social disruption survive from this period, but no one has studied these sources in depth. It is probable that the Mongols and merchant caravans inadvertently brought the plague from central Asia to the Middle East and Europe. The plague was reported in the trading cities of Constantinople and Trebizond in 1347. ## European outbreak In October 1347, a fleet of Genoese trading ships fleeing Caffa reached the port of Messina in Sicily. By the time the fleet reached Messina, all the crew members were either infected or dead. It is presumed that the ships also carried infected rats and/or fleas. Some ships were found grounded on shorelines, with no one aboard remaining alive. Looting of these lost ships also helped spread the disease. From there, the plague spread to Genoa and Venice by the turn of 1347–1348. From Italy the disease spread northwest across Europe, striking France, Spain, Portugal and England by June 1348, then turned and spread east through Germany and Scandinavia from 1348 to 1350. It was introduced in Norway in 1349 when a ship landed at Askøy, then proceeded to spread to Bjørgvin (modern Bergen). Finally it spread to north-western Russia in 1351; however, the plague largely spared some parts of Europe, including the Kingdom of Poland and isolated parts of Belgium and The Netherlands. At Siena, Agnolo di Tura wrote: "They died by the hundreds, both day and night, and all were thrown in … ditches and covered with earth. And as soon as those ditches were filled, more were dug. And I, Agnolo di Tura … buried my five children with my own hands … And so many died that all believed it was the end of the world."[30] ## Middle Eastern outbreak The plague struck various countries in the Middle East during the pandemic, leading to serious depopulation and permanent change in both economic and social structures. As it spread to western Europe, the disease also entered the region from southern Russia. By autumn 1347, the plague reached Alexandria in Egypt, probably through the port's trade with Constantinople, and ports on the Black Sea. During 1348, the disease traveled eastward to Gaza, and north along the eastern coast to cities in Lebanon, Syria and Palestine, including Ashkelon, Acre, Jerusalem, Sidon, Damascus, Homs, and Aleppo. In 1348–49, the disease reached Antioch. The city's residents fled to the north, most of them dying during the journey, but the infection had been spread to the people of Asia Minor. Mecca became infected in 1349. During the same year, records show the city of Mawsil (Mosul) suffered a massive epidemic, and the city of Baghdad experienced a second round of the disease. In 1351, Yemen experienced an outbreak of the plague. This coincided with the return of King Mujahid of Yemen from imprisonment in Cairo. His party may have brought the disease with them from Egypt. ## Recurrence In England, in the absence of census figures, historians propose a range of pre-incident population figures from as high as 7 million to as low as 4 million in 1300, and a post-incident population figure as low as 2 million.[31] By the end of 1350 the Black Death had subsided, but it never really died out in England over the next few hundred years: there were further outbreaks in 1361–62, 1369, 1379–83, 1389–93, and throughout the first half of the 15th century.[32] Plague often killed 10% of a community in less than a year - in the worst epidemics, such as at Norwich in 1579 and Newcastle in 1636, as many as 30 or 40%. The most general outbreaks in Tudor and Stuart England, all coinciding with years of plague in Germany and the Low Countries, seem to have begun in 1498, 1535, 1543, 1563, 1589, 1603, 1625 and 1636.[33] The plague repeatedly returned to haunt Europe and the Mediterranean throughout the fourteenth to seventeenth centuries, and although bubonic plague still occurs in isolated cases today, the Great Plague of London in 1665–1666 is generally recognized as one of the last major outbreaks.[34] The plague of 1575–77 claimed some 50,000 victims in Venice. In 1634, an outbreak of plague killed 15,000 Munich residents.[35] Late outbreaks in central Europe include the Italian Plague of 1629-1631, which is associated with troop movements during the Thirty Years' War, and the Great Plague of Vienna in 1679. About 200,000 people in Moscow died of the disease from 1654 to 1656.[36] The last plague outbreak ravaged Oslo in 1654.[7] In 1656 the plague killed about half of Naples's 300,000 inhabitants.[37] Amsterdam was ravaged in 1663–1664, with a mortality given as 50,000.[38] A plague epidemic that followed the Great Northern War (1700-1721, Sweden v. Russia and allies) wiped out almost 1/3 of the population in the region.[39] An estimated one-third of East Prussia's population died in the plague of 1709-1711.[40] The plague of 1710 killed two-thirds of the inhabitants of Helsinki.[41] An outbreak of plague between 1710 and 1711 claimed a third of Stockholm’s population.[42] During the Great Plague of 1738, the epidemic struck again, this time in Eastern Europe, spreading from Ukraine to the Adriatic Sea, then onwards by ship to infect some in Tunisia. The destruction in several Romanian cities such as Timişoara was formidable, claiming tens of thousands of lives. # Causes of bubonic infection ## Bubonic plague theory Plague and the ecology of Yersinia pestis in soil, and in rodent and (possibly and importantly) human ectoparasites are reviewed and summarized by Michel Drancourt in modeling sporadic, limited and large plague outbreaks.[43] Modelling of epizootic plague observed in prairie dogs suggests that occasional reservoirs of infection such as an infectious carcass, rather than "blocked fleas" are a better explanation for the observed epizootic behaviour of the disease in nature.[44] An interesting hypothesis about the epidemiology—the appearance, spread and especially disappearance—of plague from Europe is that the flea-bearing rodent reservoir of disease was eventually succeeded by another species. The black rat (Rattus rattus) was originally introduced from Asia to Europe by trade, but was subsequently displaced and succeeded throughout Europe by the bigger brown rat (Rattus norvegicus). The brown rat was not as prone to transmit the germ-bearing fleas to humans in large die-offs due to a different rat ecology.[45] The dynamic complexities of rat ecology, herd immunity in that reservoir, interaction with human ecology, secondary transmission routes between humans with or without fleas, human herd immunity and changes in each might explain the eruption, dissemination, and re-eruptions of plague that continued for centuries until its (even more) unexplained disappearance. ### Signs and symptoms The three forms of plague brought an array of signs and symptoms to those infected. The septicaemic plague is a form of "blood poisoning," and pneumonic plague is an airborne plague that attacks the lungs before the rest of the body. The classic sign of bubonic plague was the appearance of buboes in the groin, the neck and armpits, which oozed pus and bled. Most victims died within four to seven days after infection. When the plague reached Europe, it first struck port cities and then followed the trade routes, both by sea and land. The bubonic plague was the most commonly seen form during the Black Death, with a mortality rate of thirty to seventy-five percent and symptoms including fever of 38 - 41 °C (101-105 °F), headaches, painful aching joints, nausea and vomiting, and a general feeling of malaise. Of those who contracted the bubonic plague, 4 out of 5 died within eight days.[46] Pneumonic plague was the second most commonly seen form during the Black Death, with a mortality rate of ninety to ninety-five percent. Symptoms included fever, cough and blood-tinged sputum. As the disease progressed, sputum became free flowing and bright red. Septicaemic plague was the least common of the three forms, with a mortality rate close to one hundred percent. Symptoms were high fevers and purple skin patches (purpura due to DIC (Disseminated intravascular coagulation)). David Herlihy[47] identifies another potential sign of the plague: freckle-like spots and rashes. Sources from Viterbo, Italy refer to "the signs which are vulgarly called lenticulae", a word which bears resemblance to the Italian word for freckles, lentiggini. These are not the swellings of buboes, but rather "darkish points or pustules which covered large areas of the body". ## Alternative explanations ### Not bubonic plague? Although Y. pestis as the causitive agent of plague is widely accepted, recent scientific and historical investigations have led some researchers to doubt the long-held belief that the Black Death was an epidemic of bubonic plague. For example, in 2000, Gunnar Karlsson[48] pointed out that the Black Death killed between half and two-thirds of the population of Iceland, although there were no rats in Iceland at this time. Rats were accidentally introduced in the nineteenth century, and have never spread beyond a small number of urban areas attached to seaports. In the fourteenth century there were no urban settlements in Iceland. Iceland was unaffected by the later plagues which are known to have been spread by rats. However, without a rodent reservoir, pneumonic plague can be transmitted from human to human by respiratory transmission, and bubonic and septicemic plague can be transmitted from human to human by human-biting fleas. In addition, it was previously argued that tooth pulp tissue from a fourteenth-century plague cemetery in Montpellier tested positive for molecules associated with Y. pestis. Similar findings were reported in a 2007 study,[49] but other studies have yielded negative results. In September 2003, a team of researchers from Oxford University tested 121 teeth from sixty-six skeletons found in fourteenth-century mass graves. The remains showed no genetic trace of Y. pestis. In 2002, Samuel K. Cohn published the controversial article, “The Black Death: End of the Paradigm.”[50] In the article Cohn argues that the medieval and modern plagues were two distinct diseases differing in their symptoms, signs and epidemiologies.[51] Cohn asserts that the agent causing the bubonic plague, Yersinia pestis, “was first cultured at Hong Kong in 1894.” In turn, the medieval plague that struck Europe, according to Cohn, was not the bubonic plague carried by fleas on rats as traditionally viewed by scientists and historians alike.[18] Cohn’s argument that medieval plague was not rat-based is supported by his claims that the modern and medieval plagues hit in different seasons, had unparalleled cycles of recurrence, and varied in the manner in which immunity was acquired. The modern plague reaches its peak in seasons with high humidity and a temperature of between 50 °F (10 °C) and 78 °F (25.555555555556 °C), as rats’ fleas thrive in this climate.[52] In comparison, the Black Death is recorded as hitting in periods where rats’ fleas could not survive, i.e. hot Mediterranean summers above 78 °F (25.555555555556 °C).[18] In terms of recurrence, the Black Death on average did not resurface in an area for between five and fifteen years after it hit.[53] Contrastingly, modern plagues often hit an affected area yearly for an average of eight to forty years. Last, Cohn presents evidence displaying that individuals gained immunity to the Black Death during the fourteenth century, unlike the modern plague. He states that in 1348 two-thirds of those suffering from plague died in comparison to one-twentieth by 1382.[18] Statistics contrastingly display that immunity to the modern plague has not been acquired. Cohn also points out that in the latter part of the nineteenth century buboes appeared mostly on an infected person's groin, while medieval primary sources indicate that the Black Death caused buboes to appear on necks, armpits, and groins. This difference, he argues, ties in with the fact that fleas caused the modern plague and not the Black Death. Since flea bites do not usually reach beyond a person's ankles, in the modern period the groin was the nearest lymph node that could be infected. As the neck and the armpit were often infected during the medieval plague, it appears less likely that these infections were caused by fleas on rats.[54] In 1984, Graham Twigg published The Black Death: A Biological Reappraisal, where he argued that the climate and ecology of Europe and particularly England made it nearly impossible for rats and fleas to have transmitted bubonic plague. Combining information on the biology of Rattus rattus, Rattus norvegicus, and the common fleas Xenopsylla cheopis and Pulex irritans with modern studies of plague epidemiology, particularly in India, where the R. rattus is a native species and conditions are nearly ideal for plague to be spread, Twigg concludes that it would have been nearly impossible for Yersinia pestis to have been the causative agent of the plague, let alone its explosive spread across Europe. Twigg also shows that the common theory of entirely pneumonic spread does not hold up. He proposes, based on a re-examination of the evidence and symptoms, that the Black Death may actually have been an epidemic of pulmonary anthrax caused by Bacillus anthracis. ### An Ebola-like virus? In 2001, epidemiologists Susan Scott and Christopher Duncan from Liverpool University proposed the theory that the Black Death might have been caused by an Ebola-like virus, not a bacterium. Their rationale was that this plague spread much faster and the incubation period was much longer than other confirmed Y.pestis-caused plagues. A longer period of incubation will allow carriers of the infection to travel farther and infect more people than a shorter one. When the primary vector is humans, as opposed to birds, this is of great importance. Studies of English church records indicate an unusually long incubation period in excess of thirty days, which could account for the rapid spread, topping at 2 miles/day, as this was the average speed a traveler would move across the countryside. The plague also appeared in areas of Europe where rats were uncommon, areas such as Iceland. Epidemiological studies suggest the disease was transferred between humans (which happens rarely with Yersinia pestis and very rarely for Bacillus anthracis), and some genes that determine immunity to Ebola-like viruses are much more widespread in Europe than in other parts of the world. Their research and findings are thoroughly documented in Biology of Plagues. More recently the researchers have published computer modeling[55] demonstrating how the Black Death has made around 10% of Europeans resistant to HIV. ### Anthrax and others? In a similar vein, historian Norman F. Cantor, in his 2001 book In the Wake of the Plague, suggests the Black Death might have been a combination of pandemics including a form of anthrax, a cattle murrain. He cites many forms of evidence including: reported disease symptoms not in keeping with the known effects of either bubonic or pneumonic plague, the discovery of anthrax spores in a plague pit in Scotland, and the fact that meat from infected cattle was known to have been sold in many rural English areas prior to the onset of the plague. It is notable that the means of infection varied widely, from human-to-human contact as in Iceland (rare for plague and cutaneous Bacillus anthracis) to infection in the absence of living or recently dead humans, as in Sicily (which speaks against most viruses). Also, diseases with similar symptoms were generally not distinguished between in that period (see murrain above), at least not in the Christian world; Chinese and Muslim medical records can be expected to yield better information which however only pertains to the specific disease(s) which affected these areas. ### Counter-arguments Historians who believe that the Black Death was indeed caused by bubonic plague have put forth several counterarguments. The uncharacteristically rapid spread of the plague could be due to respiratory droplet transmission, and low levels of immunity in the European population at that period. Historical examples of pandemics of other diseases in populations without previous exposure, such as smallpox and tuberculosis transmitted by aerosol amongst Native Americans, show that the first instance of an epidemic spreads faster and is far more virulent than later instances among the descendants of survivors, for whom natural selection has produced characteristics that are protective against the disease. Michael McCormick, a historian offering the idea that bubonic plague was indeed the source of the Black Death, explains how archaeological research has confirmed that the black or "ship" rat was indeed present in Roman and medieval Europe. Also, the DNA of Y. pestis has been identified in the teeth of the human victims, the same DNA which has been widely believed to have come from the infected rodents.[56] He does not deny the point that there exists a pneumonic expression of Y. pestis transmitted by human-to-human contact, but he states that this does not spread as easily as previous historians have imagined. The rat, according to him, is the only plausible agent of transmission that could have led to such a wide and quick spread of the plague. This is because of rats' proclivity to associate with humans and the ability of their blood to withstand very large concentrations of the bacillus.[57] When rats died, their fleas (which were infected with bacterial blood) found new hosts in the form of humans and animals. The Black Death tapered off in the eighteenth century, and according to McCormick, a rat-based theory of transmission could explain why this occurred. The plague(s) had killed a lot of the human host population of Europe and dwindling cities meant that more people were isolated, and so geography and demography did not allow rats to have as much contact with Europeans. Greatly curtailed communication and transportation systems due to the drastic decline in human population also hindered the replenishment of devastated rat colonies.[58] # CCR5 delta 32 About 10 percent of Europeans have a gene mutation known as CCR5 delta 32 that disables a protein the Human Immunodeficiency Virus (HIV-1) uses to slip into immune system cells. Those with one copy of this gene have some immunity to HIV and those with two copies are virtually immune to the virus.[59] This genetic mutation arose about 700 years ago and it has been suggested by some researchers that survivors of bubonic plague may have selected for the mutation. However, work published in 2003 suggests that smallpox was a more likely driver for the rise of the mutation.[60] # A Malthusian crisis In addition, various historians have adopted yet another theory for the cause of the Black Plague, one that points to social, agricultural, and sometimes economic causes. Often known as the Malthusian limit, scholars use this term to express, and/or explain, certain tragedies throughout history. In his 1798 Essay on the Principle of Population, Thomas Malthus asserted that eventually humans would reproduce so greatly that they would go beyond the limits of food supplies; once they reached this point, some sort of "reckoning" was inevitable. While the Black Death may appear to be a "reckoning" of this sort, it was in fact an external, unpredictable factor and does not therefore fit into the Malthusian theory. In his book, The Black Death and the Transformation of the West, David Herlihy explores this idea of plague as an inevitable crisis wrought on humanity in order to control the population and human resources. In the book The Black Death; A Turning Point in History? (ed. William M. Bowsky) he writes “implies that the Black Death’s pivotal role in late medieval society... was now being challenged. Arguing on the basis of a neo-Malthusian economics, revisionist historians recast the Black Death as a necessary and long overdue corrective to an overpopulated Europe.” Herlihy examines the arguments against the Malthusian crisis, stating “if the Black Death was a response to excessive human numbers it should have arrived several decades earlier” due to the population growth of years before the outbreak of the Black Death. Herlihy also brings up other, biological factors that argue against the plague as a "reckoning" by arguing “the role of famines in affecting population movements is also problematic. The many famines preceding the Black Death, even the ‘great hunger’ of 1314 to 1317, did not result in any appreciable reduction in population levels”. Finally Herlihy concludes the matter stating, “the medieval experience shows us not a Malthusian crisis but a stalemate, in the sense that the community was maintaining at stable levels very large numbers over a lengthy period” and states that the phenomenon should be referred to as more of a deadlock, rather than a crisis, to describe Europe before the epidemics. # Consequences ## Depopulation See also: Medieval demography. Figures for the death toll vary widely by area and from source to source as new research and discoveries come to light. It killed an estimated 75-200 million people in the 14th century.[61][62][63] According to medieval historian Philip Daileader in 2007:[64] The trend of recent research is pointing to a figure more like 45% to 50% of the European population dying during a four-year period. There is a fair amount of geographic variation. In Mediterranean Europe and Italy, the South of France and Spain, where plague ran for about four years consecutively, it was probably closer to 80% to 75% of the population. In Germany and England . . . it was probably closer to 20%. ### Asia Estimates of the demographic impact of the plague in Asia are based on both population figures during this time and estimates of the disease's toll on population centers. The initial outbreak of plague in the Chinese province of Hubei in 1334 claimed up to ninety percent of the population, an estimated five million people. During 1353–54, outbreaks in eight distinct areas throughout the Mongol/Chinese empires may have possibly caused the death of two-thirds of China's population, often yielding an estimate of twenty-five million deaths.[65] China had several epidemics and famines from 1200 to 1350s and its population decreased from an estimated 125 million to 65 million in the late 14th century.[66][67][68] Japan and Korea had no outbreak of plague. ### Europe and Middle East It is estimated that between one-quarter and one-third of the European population (35 million people) died from the outbreak between 1348 and 1350.[8][69] Contemporary observers, such as Jean Froissart, estimated the toll to be one-third—less an accurate assessment than an allusion to the Book of Revelation meant to suggest the scope of the plague.[70] Many rural villages were depopulated, mostly the smaller communities, as the few survivors fled to larger towns and cities leaving behind abandoned villages.[71] The Black Death hit the culture of towns and cities disproportionately hard, although rural areas (where most of the population lived) were also significantly affected. A few rural areas, such as Eastern Poland and Lithuania, had such low populations and were so isolated that the plague made little progress. Parts of Hungary and, in modern Belgium, the Brabant region, Hainaut and Limbourg, as well as Santiago de Compostella, were unaffected for unknown reasons (some historians[72] have assumed that the presence of resistant blood groups in the local population helped them resist the disease, although these regions would be touched by the second plague outbreak in 1360–63 and later during the numerous resurgences of the plague). Other areas which escaped the plague were isolated mountainous regions (e.g. the Pyrenees). Larger cities were the worst off, as population densities and close living quarters made disease transmission easier. Cities were also strikingly filthy, infested with lice, fleas and rats, and subject to diseases related to malnutrition and poor hygiene. According to journalist John Kelly, "[w]oefully inadequate sanitation made medieval urban Europe so disease-ridden, no city of any size could maintain its population without a constant influx of immigrants from the countryside".(p. 68) The influx of new citizens facilitated the movement of the plague between communities, and contributed to the longevity of the plague within larger communities. In Italy, Florence's population was reduced from 110,000 or 120,000 inhabitants in 1338 to 50,000 in 1351. Between 60 to 70% of Hamburg and Bremen's population died. In Provence, Dauphiné and Normandy, historians observe a decrease of 60% of fiscal hearths. In some regions, two thirds of the population was annihilated. In the town of Givry, in the Bourgogne region in France, the friar, who used to note 28 to 29 funerals a year, recorded 649 deaths in 1348, half of them in September. About half of Perpignan's population died in several months (only two of the eight physicians survived the plague). England lost 70% of its population, which declined from 7 million before the plague, to 2 million in 1400.[73] All social classes were affected, although the lower classes, living together in unhealthy places, were most vulnerable. Alfonso XI of Castile was the only European monarch to die of the plague, but Peter IV of Aragon lost his wife, his daughter and a niece in six months. Joan of England, daughter of Edward III, died in Bordeaux on her way to Castile to marry Alfonso's son, Pedro. The Byzantine Emperor lost his son, while in the kingdom of France, Joan of Navarre, daughter of Louis X le Hutin and of Margaret of Burgundy, was killed by the plague, as well as Bonne of Luxembourg, the wife of the future John II of France. Furthermore, resurgences of the plague in later years must also be counted: in 1360–62 (the "little mortality"), in 1366–69, 1374–75, 1400, 1407, etc. The plague was not eradicated until the 19th century. The precise demographic impact of the disease in the Middle East is very difficult to calculate. Mortality was particularly high in rural areas, including significant areas of Palestine and Syria. Many surviving rural people fled, leaving their fields and crops, and entire rural provinces are recorded as being totally depopulated. Surviving records in some cities reveal a devastating number of deaths. The 1348 outbreak in Gaza left an estimated 10,000 people dead, while Aleppo recorded a death rate of 500 a day during the same year. In Damascus, at the disease's peak in September and October 1348, a thousand deaths were recorded every day, with overall mortality estimated at between 25 and 38 percent. Syria lost a total of 400,000 people by the time the epidemic subsided in March 1349. In contrast to some higher mortality estimates in Asia and Europe, scholars such as John Fields of Trinity College in Dublin believe the mortality rate in the Middle East was less than one-third of the total population, with higher rates in selected areas. ## Social and economic effects The governments of Europe had no apparent response to the crisis because no one knew its cause or how it spread. In 1348, the plague spread so rapidly that before any physicians or government authorities had time to reflect upon its origins, about a third of the European population had already perished. In crowded cities, it was not uncommon for as much as fifty percent of the population to die. Europeans living in isolated areas suffered less, and monasteries and priests were especially hard hit since they cared for the Black Death's victims.[74] Because fourteenth century healers were at a loss to explain the cause, Europeans turned to astrological forces, earthquakes, and the poisoning of wells by Jews as possible reasons for the plague's emergence.[18] No one in the fourteenth century considered rat control a way to ward off the plague, and people began to believe only God's anger could produce such horrific displays. There were many attacks against Jewish communities. In August of 1349, the Jewish communities of Mainz and Cologne were exterminated. In February of that same year, Christians murdered two thousand Jews in Strasbourg.[75] Where government authorities were concerned, most monarchs instituted measures that prohibited exports of foodstuffs, condemned black market speculators, set price controls on grain, and outlawed large-scale fishing. At best, they proved mostly unenforceable, and at worst they contributed to a continent-wide downward spiral. The hardest hit lands, like England, were unable to buy grain abroad: from France because of the prohibition, and from most of the rest of the grain producers because of crop failures from shortage of labour. Any grain that could be shipped was eventually taken by pirates or looters to be sold on the black market. Meanwhile, many of the largest countries, most notably England and Scotland, had been at war, using up much of their treasury and exacerbating inflation. In 1337, on the eve of the first wave of the Black Death, England and France went to war in what would become known as the Hundred Years' War. Malnutrition, poverty, disease and hunger, coupled with war, growing inflation and other economic concerns made Europe in the mid-fourteenth century ripe for tragedy. The plague did more than just devastate the medieval population; it caused a substantial change in economy and society in all areas of the world. Economic historians like Fernand Braudel have concluded that Black Death exacerbated a recession in the European economy that had been under way since the beginning of the century. As a consequence, social and economic change greatly accelerated during the fourteenth and fifteenth centuries. The church's power was weakened, and in some cases, the social roles it had played were taken over by secular groups. Also the plague led to peasant uprisings in many parts of Europe, such as France (the Jacquerie rebellion), Italy (the Ciompi rebellion, which swept the city of Florence), and in England (the English Peasant Revolt). Europe had been overpopulated before the plague, and a reduction of 30% to 50% of the population could have resulted in higher wages and more available land and food for peasants because of less competition for resources. However, for reasons that are still debated, population levels declined after the Black Death's first outbreak until around 1420 and did not begin to rise again until 1470, so the initial Black Death event on its own does not entirely provide a satisfactory explanation to this extended period of decline in prosperity. See Medieval demography for a more complete treatment of this issue and current theories on why improvements in living standards took longer to evolve. The great population loss brought economic changes based on increased social mobility, as depopulation further eroded the peasants' already weakened obligations to remain on their traditional holdings. In the wake of the drastic population decline brought on by the plague, authorities in Western Europe worked to maintain social order through instituting wage controls.[76] These governmental controls were set in place to ensure that workers received the same salary post-plague as they had before the onslaught of the Black Death.[18] Within England, for example, the Ordinance of Labourers, created in 1349, and the Statute of Labourers, created in 1351, restricted both wage increases and the relocation of workers.[77] If workers attempted to leave their current post, employers were given the right to have them imprisoned.[18] The Statute was strictly enforced in some areas. For example, 7,556 people in the county of Essex were fined for deviating from the Statute in 1352.[78] However, despite examples such as Essex County, the Statute quickly proved to be difficult to enforce due to the scarcity of labour. In Western Europe, the sudden shortage of cheap labour provided an incentive for landlords to compete for peasants with wages and freedoms, an innovation that, some argue, represents the roots of capitalism, and the resulting social upheaval "caused" the Renaissance, and even the Reformation. In many ways the Black Death and its aftermath improved the situation of surviving peasants, notably by the end of the 15th century. In Western Europe, labourers gained more power and were more in demand because of the shortage of labour. In gaining more power, workers following the Black Death often moved away from annual contracts in favour of taking on successive temporary jobs that offered higher wages.[79] Workers such as servants now had the opportunity to leave their current employment to seek better-paying, more attractive positions in areas previously off limits to them.[18] Another positive aspect of the period was that there was more fertile land available to the population; however, the benefits would not be fully realized until 1470, nearly 120 years later, when overall population levels finally began to rise again. In Eastern Europe, by contrast, renewed stringency of laws tied the remaining peasant population more tightly to the land than ever before through serfdom. Sparsely populated Eastern Europe was less affected by the Black Death and so peasant revolts were less common in the fourteenth and fifteenth centuries, not occurring in the east until the sixteenth through nineteenth centuries. Since it is believed to have in part caused the social upheavals of fourteenth- and fifteenth-century Western Europe, some see the Black Death as a factor in the Renaissance and even the Reformation in Western Europe. Therefore, some historians have cited the smaller impact of the plague as a contributing factor in Eastern Europe's failure to experience either of these movements on a similar scale. Extrapolating from this, the Black Death may be seen as partly responsible for Eastern Europe's considerable lag in the move to liberalise government by restricting the power of the monarch and aristocracy. A common example is that by the mid-sixteenth century, England began the process that ultimately ended serfdom there and gave rise to representative government; meanwhile, Russia did not formally abolish serfdom until an autocratic tsar decreed so in 1861. Furthermore, the plague's great population reduction brought cheaper land prices, more food for the average peasant, and a relatively large increase in per capita income among the peasantry, if not immediately, in the coming century. Since the plague left vast areas of farmland untended, they were made available for pasture and put more meat on the market; the consumption of meat and dairy products went up, as did the export of beef and butter from the Low Countries, Scandinavia and northern Germany. However, the upper class often attempted to stop these changes, initially in Western Europe, and more forcefully and successfully in Eastern Europe, by instituting sumptuary laws. These regulated what people (particularly of the peasant class) could wear, so that nobles could ensure that peasants did not begin to dress and act as a higher class member with their increased wealth. Another tactic was to fix prices and wages so that peasants could not demand more with increasing value. This was met with varying success depending on the amount of rebellion it inspired; such a law was one of the causes of the 1381 Peasants' Revolt in England. The increase in social mobility that the Black Death contributed to may have been one means by which the Great Vowel Shift was propagated. ## Persecutions As previously mentioned in reference to the plague's sociocultural impacts, renewed religious fervor and fanaticism bloomed in the wake of the Black Death. Some Christians targeted "various groups such as Jews, friars, foreigners, beggars, pilgrims",[80] lepers[81][82] and gypsies, thinking that they were to blame for the crisis. Lepers, and other individuals with skin diseases such as acne or psoriasis, were singled out and exterminated throughout Europe. Anyone with leprosy was believed to show an outward sign of a defect of the soul. Differences in cultural and lifestyle practices also led to persecution. Because Jews had a religious obligation to be ritually clean they did not use water from public wells and so were suspected of causing the plague by deliberately poisoning the wells. Typically, comparatively fewer Jews died from the Black Death, in part due to rabbinical laws that promoted habits that were generally cleaner than that of a typical medieval villager. They also were often socially isolated in Jewish ghettos and, as such, were less likely to be infected This led to lower mortality rates in the Jewish population and raised suspicions in people who had no concept of bacterial transmission. Christian mobs attacked Jewish settlements across Europe; by 1351, sixty major and 150 smaller Jewish communities had been destroyed, and more than 350 separate massacres had occurred. This persecution reflected more than ethnic hatred. In many places, attacking Jews was a way to criticize the monarchs who protected them (Jews were under the protection of the king, and often called the "royal treasure"), and monarchic fiscal policies, which were often administered by Jews. An important legacy of the Black Death was to cause the eastward movement of what was left of north European Jewry to Poland and Russia, where it remained until the twentieth century. According to Joseph P. Byrne in his book, The Black Plague, women also faced persecution during the Black Death. Muslim women in Cairo became scapegoats when the plague struck.[83] Byrne writes that in 1438, the sultan of Cairo was informed by his religious lawyers that the arrival of the plague was Allah’s punishment for the sin of fornication and that in accordance with this theory, a law was set in place stating that women were not allowed to make public appearances as they may tempt men into sin. Byrne describes that this law was only lifted when “the wealthy complained that their female servants could not shop for food.”[18] ## Religion The Black Death led to cynicism toward religious officials who could not keep their promises of curing plague victims and banishing the disease. No one, the Church included, was able to cure or accurately explain the reasons for the plague outbreaks. One theory of transmission was that it spread through air, and was referred to as miasma, or 'bad air'. This increased doubt in the clergy's abilities. Extreme alienation with the Church culminated in either support for different religious groups such as the flagellants, which from their late 13th century beginnings grew tremendously during the opening years of the Black Death, and later to a pursuit of pleasure and hedonism. It was a common belief at the time that the plague was due to God's wrath, caused by the sins of mankind; In response, the flagellants travelled from town to town, whipping themselves in an effort to mimic the sufferings of Jesus prior to his crucifixion. Originating in Germany, several miraculous tales emerged from their efforts, such as a child being revived from the dead, and a talking cow. These stories further fuelled the belief that the flagellants were more effective than church leaders. It may have been that the flagellant's later involvement in hedonism was an effort to accelerate or absorb God's wrath, to shorten the time with which others suffered. More likely, the focus of attention and popularity of their cause contributed to a sense that the world itself was ending, and that their individual actions were of no consequence. Sadly, the flagellants may have more likely contributed to the actual spreading of the disease, rather than its cure. Presumably, there were towns that the flagellants visited or passed through which were largely unaffected by the plague until that point, only to be infected by fleas carried either by the flagellant's followers, or the flagellants themselves. This is a common ironic theme in how individuals at the time dealt with the plague -- that in nearly all cases, the methods employed to defend against the plague encouraged its spread. The Black Death hit the monasteries very hard because of their proximity with the sick, who sought refuge there, so that there was a severe shortage of clergy after the epidemic cycle. This resulted in a mass influx of hastily-trained and inexperienced clergy members, many of whom knew little of the discipline and rigor of the veterans they replaced. This led to abuses by the clergy in years afterwards and a further deterioration of the position of the Church in the eyes of the people. ## Other effects After 1350, European culture in general turned very morbid. The general mood was one of pessimism, and contemporary art turned dark with representations of death. In retrospect, it seemed like everything the people thought to do at the time simply made the problem worse. For example, since many equated the plague with God's wrath against sin, and that cats were often considered in league with the Devil, cats were killed en masse. Had this bias toward cats not existed, local rodent populations could have been kept down, lessening the spread of plague-infected fleas from host to host. The practice of alchemy as medicine, previously considered to be normal for most doctors, slowly began to wane as the citizenry began to realize that it seldom affected the progress of the epidemic and that some of the potions and "cures" used by many alchemists only served to worsen the condition of the sick. Liquor, originally made by alchemists, was commonly applied as a remedy for the Black Death, and, as a result, the consumption of liquor in Europe rose dramatically after the plague. The Church often tried to meet the medical need. A plague doctor's duties were often limited to visiting victims to verify whether they had been afflicted or not. Surviving records of contracts drawn up between cities and plague doctors often gave the plague doctor enormous latitude and heavy financial compensation, given the risk of death involved for the plague doctor himself. Most plague doctors were essentially volunteers, as qualified doctors had (usually) already fled, knowing they could do nothing for those affected. Considered an early form of hazmat suit, a plague doctor's clothing consisted of: - A wide-brimmed black hat worn close to the head. At the time, a wide-brimmed black hat would have been identified a person as a doctor, much the same as how nowadays a hat may identify chefs, soldiers, and workers. The wide-brimmed hat may have also been used as partial shielding from infection. - A primitive gas mask in the shape of a bird's beak. A common belief at the time was that the plague was spread by birds. There may have been a belief that by dressing in a bird-like mask, the wearer could draw the plague away from the patient and onto the garment the plague doctor wore. The mask also included red glass eyepieces, which were thought to make the wearer impervious to evil. The beak of the mask was often filled with strongly aromatic herbs and spices to overpower the miasmas or "bad air" which was also thought to carry the plague. At the very least, it may have served a dual purpose of dulling the smell of unburied corpses, sputum, and ruptured bouboules in plague victims. - A long, black overcoat. The overcoat worn by the plague doctor was tucked in behind the beak mask at the neckline to minimize skin exposure. It extended to the feet, and was often coated head to toe in suet or wax. A coating of suet may have been used with the thought that the plague could be drawn away from the flesh of the infected victim and either trapped by the suet, or repelled by the wax. The coating of wax likely served as protection against respiratory droplet contamination, but it was not known at the time if coughing carried the plague. It was likely that the overcoat was waxed to simply prevent sputum or other bodily fluids from clinging to it. - A wooden cane. The cane was used to both direct family members to move the patient, other individuals nearby, and possibly to examine the patient with directly. - Leather breeches. Similar to waders worn by fishermen, leather breeches were worn beneath the cloak to protect the legs and groin from infection. Since the plague often tended to manifest itself first in the lymph nodes, particular attention was paid to protecting the armpits, neck, and groin. The plague doctor's clothing also had a secondary use: to intentionally frighten and warn onlookers. The bedside manner common to doctors of today did not exist at the time; part of the appearance of the plague doctor's clothing was meant to frighten onlookers, and to communicate that something very, very wrong was nearby, and that they too might become infected. It's not known how often or widespread plague doctors were, or how effective they were in treatment of the disease. It's likely that while offering some protection to the wearer, they may have actually contributed more to the spreading of the disease than its treatment, in that the plague doctor unknowingly served as a vector for infected fleas to move from host to host. Although the Black Death highlighted the shortcomings of medical science in the medieval era, it also led to positive changes in the field of medicine. As described by David Herlihy in The Black Death and the Transformation of the West, more emphasis was placed on “anatomical investigations” following the Black Death.[84] How individuals studied the human body notably changed, becoming a process that dealt more directly with the human body in varied states of sickness and health. Further, at this time, the importance of surgeons became more evident.[18] A theory put forth by Stephen O'Brien says the Black Death is likely responsible, through natural selection, for the high frequency of the CCR5-Δ32 genetic defect in people of European descent. The gene affects T cell function and provides protection against HIV, smallpox, and possibly plague,[85] though for the latter, no explanation as to how it would do that exists. This, however, seems unlikely, given that the CCR5-Δ32 gene has been found to be just as common in Bronze Age tissue samples.[86] The Black Death also inspired European architecture to move in two different directions; there was a revival of Greco-Roman styles that, in stone and paint, expressed Petrarch's love of antiquity and a further elaboration of the Gothic style.[87] Late medieval churches had impressive structures centered on verticality, where one's eye is drawn up towards the high ceiling for a religious experience bordering on the mystical. The basic Gothic style was revamped with elaborate decoration in the late medieval period. Sculptors in Italian city-states emulated the work of their Roman forefathers while sculptors in northern Europe, no doubt inspired by the devastation they had witnessed, gave way to a heightened expression of emotion and an emphasis on individual differences.[88] A tough realism came forth in architecture as in literature. Images of intense sorrow, decaying corpses, and individuals with faults as well as virtues emerged. North of the Alps, paintings reached a pinnacle in precise realism with the Flemish school of Jan Van Eyck (c. 1385-1440). The natural world was reproduced in these works with meticulous detail bordering on photography.[89] # Black Death in literature ## Contemporary The Black Death dominated art and literature throughout the generation that experienced it. Much of the most useful manifestations of the Black Death in literature, to historians, comes from the accounts of its chroniclers; contemporary accounts are often the only real way to get a sense of the horror of living through a disaster on such a scale. A few of these chroniclers were famous writers, philosophers and rulers (like Boccaccio and Petrarch). Their writings, however, did not reach the majority of the European population. For example, Petrarch's work was read mainly by wealthy nobles and merchants of Italian city-states. He wrote hundreds of letters and vernacular poetry of great distinction and passed on to later generations a revised interpretation of courtly love.[90] There was, however, one troubadour, writing in the lyric style long out of fashion, who was active in 1348. Peire Lunel de Montech composed the sorrowful sirventes "Meravilhar no·s devo pas las gens" during the height of the plague in Toulouse. Although romances continued to be popular throughout the period, the courtly tradition began to face increasing competition from ordinary writers who became involved in producing gritty realist literature, inspired by their Black Death experiences. This was a new phenomenon, made possible because vernacular education and literature, as well as the study of Latin and classical antiquity, flourished widely, making the written word steadily more accessible during the fourteenth century.[91] For example, Agnolo di Tura, of Siena, records his experience: Father abandoned child, wife husband, one brother another; for this illness seemed to strike through the breath and sight. And so they died. And none could be found to bury the dead for money or friendship. Members of a household brought their dead to a ditch as best they could, without priest, without divine offices ... great pits were dug and piled deep with the multitude of dead. And they died by the hundreds both day and night... And as soon as those ditches were filled more were dug ... And I, Agnolo di Tura, called the Fat, buried my five children with my own hands. And there were also those who were so sparsely covered with earth that the dogs dragged them forth and devoured many bodies throughout the city. There was no one who wept for any death, for all awaited death. And so many died that all believed it was the end of the world. This situation continued [from May] until September. The scene Di Tura describes is repeated over and over again all across Europe. In Sicily, Gabriele de'Mussi, a notary, tells of the early spread from Crimea: Alas! our ships enter the port, but of a thousand sailors hardly ten are spared. We reach our homes; our kindred…come from all parts to visit us. Woe to us for we cast at them the darts of death! …Going back to their homes, they in turn soon infected their whole families, who in three days succumbed, and were buried in one common grave. Priests and doctors visiting…from their duties ill, and soon were…dead. O death! cruel, bitter, impious death! …Lamenting our misery, we feared to fly, yet we dared not remain. Henry Knighton tells of the plague’s coming to England: Then the grievous plague came to the sea coasts from Southampton, and came to Bristol, and it was as if all the strength of the town had died, as if they had been hit with sudden death, for there were few who stayed in their beds more than three days, or two days, or even one half a day. Friar John Clyn witnessed its effects in Leinster, after its spread to Ireland in August 1348:[92] That disease entirely stripped vills, cities, castles and towns of inhabitaints of men, so that scarcely anyone would be able to live in them. The plague was so contagious that thous touching the dead or even the sick were immediately infected and died, and the one confessing and the confessor were together led to the grave ... many died from carbuncles and from ulcers and pustles that could be seen on shins and under the armpits; some died, as if in a frenzy, from pain of the head, others from spitting blood ... In the convent of Minors of Drogheda, twenty five, and in Dublin in the same order, twenty three died ... These cities of Dublin and Drogheda were almost destroyed and wasted of inhabitants and men so that in Dublin alone, from the beginning of August right up to Christmas, fourteen thousand men died ... The pestilence gathered strength in Kilkenny during Lent, for between Christmas day and 6 March, eight Friars Preachers died. There was scarcely a house in which only one died but commonly man and wife with their children and family going one way, namely, crossing to death. In addition to these personal accounts, many presentations of the Black Death have entered the general consciousness as great literature. For example, the major works of Boccaccio (The Decameron), Petrarch, Geoffrey Chaucer (The Canterbury Tales), and William Langland (Piers Plowman), which all discuss the Black Death, are generally recognized as some of the best works of their era. La Danse Macabre, or the Dance of death, was a contemporary allegory, expressed as art, drama, and printed work. Its theme was the universality of death, expressing the common wisdom of the time: that no matter one's station in life, the dance of death united all. It consists of the personified Death leading a row of dancing figures from all walks of life to the grave – typically with an emperor, king, pope, monk, youngster, beautiful girl, all in skeleton-state. They were produced under the impact of the Black Death, reminding people of how fragile their lives were and how vain the glories of earthly life. The earliest artistic example is from the frescoed cemetery of the Church of the Holy Innocents in Paris (1424). There are also works by Konrad Witz in Basel (1440), Bernt Notke in Lübeck (1463) and woodcuts by Hans Holbein the Younger (1538). Israil Bercovici claims that the Danse Macabre originated among Sephardic Jews in fourteenth century Spain (Bercovici, 1992, p. 27). The poem "The Rattle Bag" by the Welsh poet Dafydd ap Gwilym (1315-1350 or 1340-1370) has many elements that suggest that it was written as a reflection of the hardships he endured during the Black Death. It also reflects his personal belief that the Black Death was the end of humanity, the Apocalypse, as suggested by his multiple biblical references, particularly the events described in the Book of Revelation. Thomas Nashe also wrote a sonnet about the plague entitled "A Litany in Time of Plague" which was part of Summers last will and Testament (1592). He made countryside visits to remove himself from London in fear of the plague. Additionally see Aleksandr Pushkin's verse play, "Feast in the Time of the Plague". The Black Death quickly entered common folklore in many European countries. In Northern Europe, the plague was personalized as an old, bent woman covered and hooded in black, carrying a broom and a rake. Norwegians told that if she used the rake, some of the population involved might survive, escaping through the teeth of the rake. If she on the other hand used the broom, then the entire population in the area were doomed. The Plague-hag, or Pesta, were vividly drawn by the painter Theodor Kittelsen. Women during and after the Black Death also benefited from the growing importance of vernacular literature because a broader cultural forum became available to them which had previously been restricted to men by the Latin church. And so, they began writing and fostering through patronage the writings and translations of others.[93] For example, in France, Christine de Pizan (1364-1430) became the first woman in Europe to support herself by writing. She wrote in many different literary forms, such as an autobiography and books of moral advice for men and women, as well as poetry on a wide range of topics. In her treatise The Letter to the God of Love, she effectively rebutted Jean de Meun's anti-feminist diatribes found in his conclusion of Romance of the Rose.[94] Her rebuttal is important because it marked the first instance in European history where a woman wrote about the slanders women had long endured. It also led to a debate among de Meun and Pizan sympathizers which lasted until the sixteenth century.[18] ## Modern The Black Plague has been used as a subject or as a setting in modern literature and also media. This may be due to the era's resounding impact on ancient and modern history, and its symbolism and connotations. Albert Camus's novel La Peste deals with the coming of a plague to Algeria. Hermann Hesse's novel Narcissus and Goldmund depicts two monks living during the Black Death, one of whom leaves the monastery to wander around the country, seeing the epidemic's effects firsthand. Norman F. Cantor's novel "In the Wake of the Plague" New York Times Bestseller "Cantor illuminates intricate connections that alter the course of culture, religion, and peace in incalculable ways." - Boston Globe Alessandro Manzoni's novel The Betrothed contains an extraordinary description of the plague that struck Milan in 1630. Although a work of fiction, Manzoni's description of the conditions and events in plague-ravaged Milan are completely historical and extensively documented from primary sources researched by Manzoni. Roger Zelazny's novel Nine Princes in Amber has his protagonist abducted from his birthland and taken to plague-torn England to die. Edgar Allan Poe's short story "The Masque of the Red Death" (1842) is set in an unnamed country during a fictional plague that bears strong resemblance to the Black Death. This possibility is furthered by the climax of the story taking place in a black room.[95] Nobel prizewinner Sigrid Undset's novel Kristin Lavransdatter features the outbreak of the plague in 14th century Norway. Year of Wonders by Geraldine Brooks (2001) is a NY Times and Washington Post Notable Book set in 1666 England. It chronicles the impact of the plague upon the residents of an isolated mountain village, who choose to quarantine themselves rather than contribute to the spread of the disease. Connie Willis's Hugo Award-winning science fiction novel Doomsday Book imagines a future in which historians do field work by travelling into the past as observers. The protagonist, a historian, is sent to the wrong year, arriving in England just as the Black Death is starting. Also, In Michael Crichton's book Timeline, a character is transported through time to a village that is apparently affected by the Black Death. In Kim Stanley Robinson's alternate history novel The Years of Rice and Salt, a Black Death with a virtually 100% mortality rate depopulates Medieval Europe; Western Christendom is utterly destroyed as a civilization and Europe plays no major role in world history. Three novels by Ann Benson play on parallels between the Black Death and emerging diseases in the modern world. In The Plague Tales (1998), Burning Road (2000) and The Physician's Tale (2007), Benson shifts back and forth between the fourteenth century and a world in the near future that has been devastated by an antibiotic-resistant bacterium. She weaves in allusions to many of the contemporary sources, and even modern fiction like Geraldine Brooks' Year of Wonders. Eifelheim by Michael Flynn depicts the interactions between an isolated German village and a group of stranded extraterrestrials as the plague advances (1348-9). Temple of the Winds, the fourth book in the fantasy series The Sword of Truth by Terry Goodkind, centers around a plague that is very similar to the Black Death. Melanie Rawn's fantasy novel, Dragon Prince, shows how a plague-like epidemic affects nobility somewhat less than commoners. It has been alleged (since 1961) that the Black Death inspired one of the most enduring nursery rhymes in the English language, Ring a Ring o' Roses, a pocket full of posies, / Ashes, ashes (or ah-tishoo ah-tishoo), we all fall down. However, there are no written records of the rhyme before the late 19th century and not all of its many variants refer to ashes, sneezing, falling down or anything else that could be connected to the Black Death.[96] The relatively new medium of film has given writers and film producers an opportunity to portray the plague with more visual realism. One of the best known and most expansive depictions of the black plague as art is the movie classic The Seventh Seal, a 1957 film directed by Ingmar Bergman. The knight returns from the Crusades and finds that his home country is ravaged by the Black Death. To his dismay, but not surprise, he discovers that Death has come for him too. The final scene of The Seventh Seal depicts a kind of Danse Macabre. The 1988 science fiction film The Navigator: A Medieval Odyssey portrays a group of 14th-century English villagers who, with the aid of a boy's clairvoyant visions, dig a tunnel to 20th-century New Zealand to escape the Black Death. Panic in the Streets is a black and white, 96-minute film directed by Elia Kazan and released in 1950 by 20th Century Fox. It is film noir semidocumentary shot exclusively on location in New Orleans, Louisiana and featuring numerous New Orleans citizens in speaking and non-speaking roles. The film tells the story of Clinton Reed, an officer of the U.S. Public Health Service (played by Richard Widmark) and a police captain (Paul Douglas) who have only a day or two in which to prevent an epidemic of pneumonic plague after Reed determines a waterfront homicide victim is an index case. It was the film debut of Jack Palance and Zero Mostel. The Black Metal band 1349 is named after the year the Black Death spread through Norway. Danse Macabre by The Faint is a techno dance album alluding to the Black Death. Piers Anthony's 1988 novel, For Love of Evil, is sixth in his Incarnations of Immortality series. In this series, several major forces in mankind's existence are offices held by mortals for various lengths of time before passing to a successor. The Black Death was brought to Europe by Satan to exact revenge on the office of Nature and also discomfited the offices of Death and Fate. Ken Follett's 2007 novel, World Without End, deals with the lives of four children who live through the Black Death from 1327 to 1361. The "Bring out your dead!" scene in the Monty Python movie Monty Python and the Holy Grail famously deals with the ubiquity of plague-related deaths in medieval villages, although the film is explicitly set in 932, and King Arthur would suggest an even earlier date than that. In Garth Nix's book Mister Monday the main characters end up in the Black Death ridden streets. It depicts the roads as covered with piles of the dead. In the beginning of the videogame Neverwinter Nights the player is in a city which suffers from a fictitious, epidemic disease called the "Howling Death", which bears some resemblance to the Black Death.	https://www.wikidoc.org/index.php/Black_Death
bbea5e1eece5a9e6599730bb916332bcd5b87236	wikidoc	Melancholia	Melancholia # Overview Melancholia (Greek μελανχολία), in contemporary usage, is a mood disorder of non-specific depression, characterized by low levels of enthusiasm and low levels of eagerness for activity. In a modern context, "melancholy" applies only to the mental or emotional symptoms of depression or despondency; historically, "melancholia" could be physical as well as mental, and melancholic conditions were classified as such by their common cause rather than by their properties. Similarly, melancholia in ancient usage also encompassed mental disorders which would later be differentiated as schizophrenias or bipolar disorders. # History The name "melancholia" comes from the old medical theory of the four humours: disease being caused by an imbalance in one or other of the four basic bodily fluids, or humours. Personality types were similarly determined by the dominant humour in a particular person. Melancholia was caused by an excess of black bile; hence the name, which means 'black bile' (Ancient Greek μελας, melas, "black", + χολη, kholé, "bile"); a person whose constitution tended to have a preponderance of black bile had a melancholic disposition. See also: sanguine, phlegmatic, choleric Melancholia was described as a distinct disease with particular mental and physical symptoms as early as the fifth and fourth centuries BC. Hippocrates, in his Aphorisms, characterized all "fears and despondencies, if they last a long time" as being symptomatic of melancholia. The most extended treatment of melancholia comes from Robert Burton, whose The Anatomy of Melancholy treats the subject from both a literary and a medical perspective. Burton wrote in the 16th century that music and dance were critical in treating mental illness, especially melancholia. In November 2006, Dr. Michael J. Crawford and his colleagues again found that music therapy helped the outcomes of Schizophrenic patients. A famous allegorical engraving by Albrecht Dürer is entitled Melencolia I. This engraving portrays melancholia as the state of waiting for inspiration to strike, and not necessarily as a depressive affliction. Amongst other allegorical symbols, the picture includes a magic square, and a truncated rhombohedron . The image in turn inspired a passage in The City of Dreadful Night by James Thomson (B.V.), and, a few years later, a sonnet by Edward Dowden. # The cult of melancholia During the early 17th century, a curious cultural and literary cult of melancholia arose in England. It was believed that religious uncertainties caused by the English Reformation and a greater attention being paid to issues of sin, damnation, and salvation, led to this effect. In music, the post-Elizabethan cult of melancholia is associated with John Dowland, whose motto was Semper Dowland, semper dolens. ("Always Dowland, always mourning.") The melancholy man, known to contemporaries as a "malcontent," is epitomized by Shakespeare's Prince Hamlet, the "Melancholy Dane." Another literary expression of this cultural mood comes from the death-obsessed later works of John Donne. Other major melancholic authors include Sir Thomas Browne, and Jeremy Taylor, whose Hydriotaphia, Urn Burial and Holy Living and Holy Dying, respectively, contain extensive meditations on death. A similar phenomenon, though not under the same name, occurred during Romanticism, with such works as The Sorrows of Young Werther by Goethe. In the 20th century, much of the counterculture of modernism was fueled by comparable alienation and a sense of purposelessness called "anomie." # Melancholy in Arab culture The Arabic word found as ḥuzn and ḥazan in the Qur'an and hüzün in modern Turkish refers to the pain and sorrow over a loss, death of relatives in the case of the Qur'an. Two schools further interpreted this feeling. The first sees it as a sign that one is too attached to the material world, while Sufism took it to represent a feeling of personal insuffiency, that one was not getting close enough to God and did not or could not do enough for God in this world. The Turkish writer Orhan Pamuk in further elaborates on the added meaning hüzün has acquired in modern Turkish. It has come to denote a sense of failure in life, lack of initiative and to retreat into oneself, symptoms quite similar to melancholia. According to Pamuk it was a defining character of cultural works from Istanbul after the fall of the Ottoman empire. One may see similarities with how melancholic romantic paintings in the west sometimes used ruins from the age of the roman empire as a backdrop. As a parallel with physicians of classical Greece, ancient Arabic physicians also categorized ḥuzn as a disease. Al-Kindi (c. 801–873 CE) links it with disease-like mental states like anger, passion, hatred and depression, while Avicenna (980–1037 CE) diagnosed ḥuzn in a lovesick man if his pulse increased drastically when the name of the girl he loved was spoken. Avicenna discuss, in remarkable similarity with Robert Burton, causes like fear of death, intrigues, love, and food and treatments combining medicine and philosophy. Including rational thought, morale, discipline, fasting and coming to terms with the catastrophe. The various uses of ḥuzn and hüzün thus describe melancholy from a certain vantage point, show similarities with Female hysteria in the case of Avicenna's patient and in a religious context it is not unlike sloth, which by Dante was defined as "failure to love God with all one's heart, all one's mind and all one's soul". Thomas Aquinas described sloth as "an oppressive sorrow, which, to wit, so weighs upon man's mind, that he wants to do nothing". # Notes - ↑ Hippocrates, Aphorisms, Section 6.23 - ↑ cf. The Anatomy of Melancholy, Robert Burton, subsection 3, on and after line 3480, "Music a Remedy": But to leave all declamatory speeches in praise of divine music, I will confine myself to my proper subject: besides that excellent power it hath to expel many other diseases, it is a sovereign remedy against despair and melancholy, and will drive away the devil himself. Canus, a Rhodian fiddler, in Philostratus, when Apollonius was inquisitive to know what he could do with his pipe, told him, "That he would make a melancholy man merry, and him that was merry much merrier than before, a lover more enamoured, a religious man more devout." Ismenias the Theban, Chiron the centaur, is said to have cured this and many other diseases by music alone: as now they do those, saith Bodine, that are troubled with St. Vitus's Bedlam dance. - ↑ "Humanities are the Hormones: A Tarantella Comes to Newfoundland. What should we do about it?" by Dr. John Crellin, MUNMED, newsletter of the Faculty of Medicine, Memorial University of Newfoundland, 1996. - ↑ Aung, Steven K.H., Lee, Mathew H.M. (2004). "Music, Sounds, Medicine, and Meditation: An Integrative Approach to the Healing Arts". Alternative & Complementary Therapies. 10 (5): 266–270. doi:10.1089/act.2004.10.266.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} - ↑ Dr. Michael J. Crawford page at Imperial College London, Faculty of Medicine, Department of Psychological Medicine. - ↑ Crawford, Mike J. (2006). "Music therapy for in-patients with schizophrenia: Exploratory randomised controlled trial". The British Journal of Psychiatry (2006). 189: 405–409. doi:10.1192/bjp.bp.105.015073. PMID 17077429. Unknown parameter \|quotes= ignored (help); Unknown parameter \|month= ignored (help); Unknown parameter \|coauthors= ignored (help) - ↑ Jump up to: 7.0 7.1 'Istanbul', chapter 10, (2003) Orhan Pamuk - ↑ Avicenna, Fi'l-Ḥuzn, (About Ḥuzn) - ↑ "Summa Theologica", Thomas Aquinas	Melancholia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] # Overview Melancholia (Greek μελανχολία), in contemporary usage, is a mood disorder of non-specific depression, characterized by low levels of enthusiasm and low levels of eagerness for activity. In a modern context, "melancholy" applies only to the mental or emotional symptoms of depression or despondency; historically, "melancholia" could be physical as well as mental, and melancholic conditions were classified as such by their common cause rather than by their properties. Similarly, melancholia in ancient usage also encompassed mental disorders which would later be differentiated as schizophrenias or bipolar disorders. # History The name "melancholia" comes from the old medical theory of the four humours: disease being caused by an imbalance in one or other of the four basic bodily fluids, or humours. Personality types were similarly determined by the dominant humour in a particular person. Melancholia was caused by an excess of black bile; hence the name, which means 'black bile' (Ancient Greek μελας, melas, "black", + χολη, kholé, "bile"); a person whose constitution tended to have a preponderance of black bile had a melancholic disposition. See also: sanguine, phlegmatic, choleric Melancholia was described as a distinct disease with particular mental and physical symptoms as early as the fifth and fourth centuries BC. Hippocrates, in his Aphorisms, characterized all "fears and despondencies, if they last a long time" as being symptomatic of melancholia.[1] The most extended treatment of melancholia comes from Robert Burton, whose The Anatomy of Melancholy treats the subject from both a literary and a medical perspective. Burton wrote in the 16th century that music and dance were critical in treating mental illness, especially melancholia.[2][3][4] In November 2006, Dr. Michael J. Crawford [5] and his colleagues again found that music therapy helped the outcomes of Schizophrenic patients. [6] A famous allegorical engraving by Albrecht Dürer is entitled Melencolia I. This engraving portrays melancholia as the state of waiting for inspiration to strike, and not necessarily as a depressive affliction. Amongst other allegorical symbols, the picture includes a magic square, and a truncated rhombohedron [3]. The image in turn inspired a passage in The City of Dreadful Night by James Thomson (B.V.), and, a few years later, a sonnet by Edward Dowden. # The cult of melancholia During the early 17th century, a curious cultural and literary cult of melancholia arose in England. It was believed that religious uncertainties caused by the English Reformation and a greater attention being paid to issues of sin, damnation, and salvation, led to this effect. In music, the post-Elizabethan cult of melancholia is associated with John Dowland, whose motto was Semper Dowland, semper dolens. ("Always Dowland, always mourning.") The melancholy man, known to contemporaries as a "malcontent," is epitomized by Shakespeare's Prince Hamlet, the "Melancholy Dane." Another literary expression of this cultural mood comes from the death-obsessed later works of John Donne. Other major melancholic authors include Sir Thomas Browne, and Jeremy Taylor, whose Hydriotaphia, Urn Burial and Holy Living and Holy Dying, respectively, contain extensive meditations on death. A similar phenomenon, though not under the same name, occurred during Romanticism, with such works as The Sorrows of Young Werther by Goethe. In the 20th century, much of the counterculture of modernism was fueled by comparable alienation and a sense of purposelessness called "anomie." # Melancholy in Arab culture The Arabic word found as ḥuzn and ḥazan in the Qur'an and hüzün in modern Turkish refers to the pain and sorrow over a loss, death of relatives in the case of the Qur'an. Two schools further interpreted this feeling. The first sees it as a sign that one is too attached to the material world, while Sufism took it to represent a feeling of personal insuffiency, that one was not getting close enough to God and did not or could not do enough for God in this world.[7] The Turkish writer Orhan Pamuk in [7] further elaborates on the added meaning hüzün has acquired in modern Turkish. It has come to denote a sense of failure in life, lack of initiative and to retreat into oneself, symptoms quite similar to melancholia. According to Pamuk it was a defining character of cultural works from Istanbul after the fall of the Ottoman empire. One may see similarities with how melancholic romantic paintings in the west sometimes used ruins from the age of the roman empire as a backdrop. As a parallel with physicians of classical Greece, ancient Arabic physicians also categorized ḥuzn as a disease. Al-Kindi (c. 801–873 CE) links it with disease-like mental states like anger, passion, hatred and depression, while Avicenna (980–1037 CE) diagnosed ḥuzn in a lovesick man if his pulse increased drastically when the name of the girl he loved was spoken. [8] Avicenna discuss, in remarkable similarity with Robert Burton, causes like fear of death, intrigues, love, and food and treatments combining medicine and philosophy. Including rational thought, morale, discipline, fasting and coming to terms with the catastrophe. The various uses of ḥuzn and hüzün thus describe melancholy from a certain vantage point, show similarities with Female hysteria in the case of Avicenna's patient and in a religious context it is not unlike sloth, which by Dante was defined as "failure to love God with all one's heart, all one's mind and all one's soul". Thomas Aquinas described sloth as "an oppressive sorrow, which, to wit, so weighs upon man's mind, that he wants to do nothing". [9] # Notes - ↑ Hippocrates, Aphorisms, Section 6.23 - ↑ cf. The Anatomy of Melancholy, Robert Burton, subsection 3, on and after line 3480, "Music a Remedy": But to leave all declamatory speeches in praise [3481]of divine music, I will confine myself to my proper subject: besides that excellent power it hath to expel many other diseases, it is a sovereign remedy against [3482] despair and melancholy, and will drive away the devil himself. Canus, a Rhodian fiddler, in [3483]Philostratus, when Apollonius was inquisitive to know what he could do with his pipe, told him, "That he would make a melancholy man merry, and him that was merry much merrier than before, a lover more enamoured, a religious man more devout." Ismenias the Theban, [3484]Chiron the centaur, is said to have cured this and many other diseases by music alone: as now they do those, saith [3485]Bodine, that are troubled with St. Vitus's Bedlam dance. [1] - ↑ "Humanities are the Hormones: A Tarantella Comes to Newfoundland. What should we do about it?" by Dr. John Crellin, MUNMED, newsletter of the Faculty of Medicine, Memorial University of Newfoundland, 1996. - ↑ Aung, Steven K.H., Lee, Mathew H.M. (2004). "Music, Sounds, Medicine, and Meditation: An Integrative Approach to the Healing Arts". Alternative & Complementary Therapies. 10 (5): 266–270. doi:10.1089/act.2004.10.266.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} - ↑ Dr. Michael J. Crawford page at Imperial College London, Faculty of Medicine, Department of Psychological Medicine. - ↑ Crawford, Mike J. (2006). "Music therapy for in-patients with schizophrenia: Exploratory randomised controlled trial". The British Journal of Psychiatry (2006). 189: 405–409. doi:10.1192/bjp.bp.105.015073. PMID 17077429. Unknown parameter \|quotes= ignored (help); Unknown parameter \|month= ignored (help); Unknown parameter \|coauthors= ignored (help) - ↑ Jump up to: 7.0 7.1 'Istanbul', chapter 10, (2003) Orhan Pamuk - ↑ Avicenna, Fi'l-Ḥuzn, (About Ḥuzn) - ↑ "Summa Theologica", Thomas Aquinas	https://www.wikidoc.org/index.php/Black_bile
ccd657d74a78611932ad7ad42d928dbb7fb17bd4	wikidoc	Hypercapnia	Hypercapnia Synonyms and keywords: Hypercapnea; hypercarbia; blood carbon dioxide raised # Overview Hypercapnia is a condition where there is too much carbon dioxide (CO2) in the blood. Carbon dioxide is a gaseous product of the body's metabolism and is normally expelled through the lungs. Hypercapnia is the opposite of hypocapnia. # Causes Hypercapnia is generally caused by hypoventilation, lung disease, or diminished consciousness. It may also be caused by exposure to environments containing abnormally high concentrations of carbon dioxide (usually due to volcanic or geothermal causes), or by rebreathing exhaled carbon dioxide. It can also be an initial effect of administering supplemental oxygen on a patient with sleep apnea. In this situation the hypercapnia can also be accompanied by respiratory acidosis. # Diagnosis ## Symptoms Symptoms of early hypercapnia, where arterial carbon dioxide pressure, PaCO2, is elevated but not extremely so, include flushed skin, full pulse, extrasystoles, muscle twitches, hand flaps, reduced neural activity, and possibly a raised blood pressure. In severe hypercapnia (generally PaCO2 greater than 100 hPa or 75 mmHg), symptomatology progresses to disorientation, panic, hyperventilation, convulsions, unconsciousness, and eventually death. ## Laboratory Findings Hypercapnia is generally defined as a blood gas carbon dioxide level over 45 mmHg. Since carbon dioxide is in equilibrium with bicarbonate in the blood, hypercapnia can also result in a high serum bicarbonate (HCO3-) concentration. Normal bicarbonate concentrations vary from 22 to 28 milligrams per deciliter. # During Diving Normal respiration in divers results in alveolar hypoventilation resulting in inadequate CO2 elimination or hypercapnia. Lanphier's work at the US Naval Experimental Diving Unit answered the question "why don't divers breathe enough?": - Higher Inspired Oxygen (PiO2) at 4 ata (404 kPa) accounted for not more than 25% of the elevation in End Tidal CO2 (etCO2) above values found at the same work rate when breathing air just below the surface. - Increased Work of Breathing accounted for most of the elevation of PACO2 (alveolar gas equation) in exposures above 1 ata (101 kPa), as indicated by the results when helium was substituted for nitrogen at 4 ata (404 kPa). - Inadequate ventilatory response to exertion was indicated by the fact that, despite resting values in the normal range, PetCO2 rose markedly with exertion even when the divers breathed air at a depth of only a few feet. ## Additional Sources of CO2 in diving There are a variety of reasons for carbon dioxide not being expelled completely when the diver exhales: - The diver is exhaling into a vessel that does not allow all the CO2 to escape to the environment, such as a long snorkel, full face diving mask, or diving helmet. The diver then re-inhales from that vessel (Increased deadspace). - The carbon dioxide scrubber in the diver's rebreather is failing to remove sufficient carbon dioxide from the loop (Higher inspired CO2). - The diver is over-exercising, producing excess carbon dioxide due to elevated metabolic activity. - The density of the breathing gas is higher at depth, so the effort required to fully inhale and exhale has increased, making breathing more difficult and less efficient (Work of breathing). The higher gas density also causes gas mixing within the lung to be less efficient, thus increasing the deadspace (wasted breathing). - The diver is deliberately hypoventilating, known as "skip breathing" (see below). ## Skip breathing Skip breathing is a controversial technique to conserve breathing gas when using open-circuit scuba, which consists of briefly holding one's breath between inhalation and exhalation (i.e. "skipping" a breath). It leads to CO2 not being exhaled efficiently. There is also an increased risk of burst lung from holding the breath while ascending. Skip breathing is counter productive with a rebreather where the act of breathing pumps the gas around the "loop" pushing carbon dioxide through the scrubber and mixing freshly injected oxygen. ## Rebreathers In closed circuit SCUBA (rebreather) diving, exhaled carbon dioxide must be removed from the breathing system, usually by a scrubber containing a solid chemical compound with a high affinity for CO2, such as soda lime. If not removed from the system, it may be re-inhaled, causing an increase in the inhaled concentration. # Related Chapters - Permissive hypercapnia - Hypocapnia, decreased level of carbon dioxide - Respiratory Physiology - Ocean acidification	Hypercapnia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: Hypercapnea; hypercarbia; blood carbon dioxide raised # Overview Hypercapnia is a condition where there is too much carbon dioxide (CO2) in the blood. Carbon dioxide is a gaseous product of the body's metabolism and is normally expelled through the lungs. Hypercapnia is the opposite of hypocapnia. # Causes Hypercapnia is generally caused by hypoventilation, lung disease, or diminished consciousness. It may also be caused by exposure to environments containing abnormally high concentrations of carbon dioxide (usually due to volcanic or geothermal causes), or by rebreathing exhaled carbon dioxide. It can also be an initial effect of administering supplemental oxygen on a patient with sleep apnea. In this situation the hypercapnia can also be accompanied by respiratory acidosis. [1] # Diagnosis ## Symptoms Symptoms of early hypercapnia, where arterial carbon dioxide pressure, PaCO2, is elevated but not extremely so, include flushed skin, full pulse, extrasystoles, muscle twitches, hand flaps, reduced neural activity, and possibly a raised blood pressure. In severe hypercapnia (generally PaCO2 greater than 100 hPa or 75 mmHg), symptomatology progresses to disorientation, panic, hyperventilation, convulsions, unconsciousness, and eventually death.[2][3] ## Laboratory Findings Hypercapnia is generally defined as a blood gas carbon dioxide level over 45 mmHg. Since carbon dioxide is in equilibrium with bicarbonate in the blood, hypercapnia can also result in a high serum bicarbonate (HCO3-) concentration. Normal bicarbonate concentrations vary from 22 to 28 milligrams per deciliter. # During Diving Normal respiration in divers results in alveolar hypoventilation resulting in inadequate CO2 elimination or hypercapnia. Lanphier's work at the US Naval Experimental Diving Unit answered the question "why don't divers breathe enough?":[4] - Higher Inspired Oxygen (PiO2) at 4 ata (404 kPa) accounted for not more than 25% of the elevation in End Tidal CO2 (etCO2) above values found at the same work rate when breathing air just below the surface.[5][6][7][8] - Increased Work of Breathing accounted for most of the elevation of PACO2 (alveolar gas equation) in exposures above 1 ata (101 kPa), as indicated by the results when helium was substituted for nitrogen at 4 ata (404 kPa).[5][6][7][8] - Inadequate ventilatory response to exertion was indicated by the fact that, despite resting values in the normal range, PetCO2 rose markedly with exertion even when the divers breathed air at a depth of only a few feet.[5][6][7][8] ## Additional Sources of CO2 in diving There are a variety of reasons for carbon dioxide not being expelled completely when the diver exhales: - The diver is exhaling into a vessel that does not allow all the CO2 to escape to the environment, such as a long snorkel, full face diving mask, or diving helmet. The diver then re-inhales from that vessel (Increased deadspace).[8] - The carbon dioxide scrubber in the diver's rebreather is failing to remove sufficient carbon dioxide from the loop (Higher inspired CO2). - The diver is over-exercising, producing excess carbon dioxide due to elevated metabolic activity. - The density of the breathing gas is higher at depth, so the effort required to fully inhale and exhale has increased, making breathing more difficult and less efficient (Work of breathing).[4] The higher gas density also causes gas mixing within the lung to be less efficient, thus increasing the deadspace (wasted breathing).[8] - The diver is deliberately hypoventilating, known as "skip breathing" (see below). ## Skip breathing Skip breathing is a controversial technique to conserve breathing gas when using open-circuit scuba, which consists of briefly holding one's breath between inhalation and exhalation (i.e. "skipping" a breath). It leads to CO2 not being exhaled efficiently. There is also an increased risk of burst lung from holding the breath while ascending. Skip breathing is counter productive with a rebreather where the act of breathing pumps the gas around the "loop" pushing carbon dioxide through the scrubber and mixing freshly injected oxygen. ## Rebreathers In closed circuit SCUBA (rebreather) diving, exhaled carbon dioxide must be removed from the breathing system, usually by a scrubber containing a solid chemical compound with a high affinity for CO2, such as soda lime. If not removed from the system, it may be re-inhaled, causing an increase in the inhaled concentration. # Related Chapters - Permissive hypercapnia - Hypocapnia, decreased level of carbon dioxide - Respiratory Physiology - Ocean acidification	https://www.wikidoc.org/index.php/Blood_carbon_dioxide_raised
2fe124fc066d78b141fa18a3fff460aa03a377b9	wikidoc	Coagulation	Coagulation # Overview Coagulation is a complex process by which blood forms solid clots. It is an important part of hemostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a platelet- and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding and/or clotting and embolism. Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and a protein (coagulation factor) component. The system in humans has been the most extensively researched and therefore is the best understood. Coagulation is initiated almost instantly after an injury to the blood vessel damages the endothelium (lining of the vessel). Platelets immediately form a hemostatic plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously—proteins in the blood plasma, called coagulation factors, respond in a complex cascade to form fibrin strands which strengthen the platelet plug. # Physiology ## Platelet Activation Damage to blood vessel walls exposes collagen normally present under the endothelium. Circulating platelets bind to the collagen with the surface collagen-specific glycoprotein Ia/IIa receptor. This adhesion is strengthened further by the large multimeric circulating protein von Willebrand factor (vWF), which forms links between the platelet glycoprotein Ib/IX/V and collagen fibrils. The platelets are then activated and release the contents of their granules into the plasma, in turn activating other platelets. The platelets undergo a change in their shape which exposes a phospholipid surface for those coagulation factors that require it. Fibrinogen links adjacent platelets by forming links via the glycoprotein IIb/IIIa. In addition, thrombin activates platelets. ## The Coagulation Cascade The coagulation cascade of secondary hemostasis has two pathways, the contact activation pathway (formerly known as the intrinsic pathway) and the tissue factor pathway (formerly known as the extrinsic pathway) that lead to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form. The coagulation factors are generally serine proteases (enzymes). There are some exceptions. For example, FVIII and FV are glycoproteins and Factor XIII is a transglutaminase. Serine proteases act by cleaving other proteins at specific sites. The coagulation factors circulate as inactive zymogens. The coagulation cascade is classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin. ### Tissue Factor Pathway The main role of the tissue factor pathway is to generate a "thrombin burst", a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released instantaneously. FVIIa circulates in a higher amount than any other activated coagulation factor. - Following damage to the blood vessel, endothelium Tissue Factor (TF) is released, forming a complex with FVII and in so doing, activating it (TF-FVIIa). - TF-FVIIa activates FIX and FX. - FVII is itself activated by thrombin, FXIa, plasmin, FXII and FXa. - The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI). - FXa and its co-factor FVa form the prothrombinase complex which activates prothrombin to thrombin. - Thrombin then activates other components of the coagulation cascade, including FV and FVII (which activates FXI, which in turn activates FIX), and activates and releases FVIII from being bound to vWF. - FVIIIa is the co-factor of FIXa and together they form the "tenase" complex which activates FX and so the cycle continues. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.) ### Contact Activation Pathway The contact activation pathway begins with formation of the primary complex on collagen by high-molecular weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder. ### Final Common Pathway Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic plug. In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin), and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers. Following activation by the contact factor or tissue factor pathways the coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by the anticoagulant pathways. ## Cofactors Various substances are required for the proper functioning of the coagulation cascade: - Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on FXa and FIXa to the phospholipid surfaces expressed by platelets as well as procoagulant microparticles or microvesicles shedded from them. Calcium is also required at other points in the coagulation cascade. - Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z. Deficiency of vitamin K (e.g. in malabsorption), use of inhibiting anticoagulants (warfarin, acenocoumarol and phenprocoumon) or disease (hepatocellular carcinoma) impairs the function of the enzyme and leads to the formation of PIVKAs (proteins formed in vitamin K absence) this causes partial or non gamma carboxylation and affects the coagulation factors ability to bind to expressed phospholipid. ## Inhibitors Three mechanisms keep the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis: - Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C (APC). The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa. Quantitative or qualitative deficiency of either may lead to thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by having the "Leiden" variant of Factor V or high levels of FVIII also may lead to a thrombotic tendency. - Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases; thrombin and FXa, as well as FXIIa, and FIXa. It is constantly active, but its adhesion to these factors is increased by the presence of heparan sulfate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to F Xa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g. in proteinuria) leads to thrombophilia. - Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related activation of F IX and F X after its original initiation. ## Fibrinolysis Eventually, all blood clots are reorganised and resorbed by a process termed fibrinolysis. The main enzyme responsible for this process (plasmin) is regulated by various activators and inhibitors. # Video Explaining Coagulation Cascade # Tests used to Assess the Function of Coagulation Cascade Numerous tests are used to assess the function of the coagulation system: - Common: aPTT, PT (also used to determine INR), fibrinogen testing (often by the Clauss method), platelet count, platelet function testing (often by PFA-100). - Other: TCT, bleeding time, mixing test (whether an abnormality corrects if the patient's plasma is mixed with normal plasma), coagulation factor assays, antiphosholipid antibodies, D-dimer, genetic tests (eg. factor V Leiden, prothrombin mutation G20210A), dilute Russell's viper venom time (dRVVT), miscellanous platelet function tests, thromboelastography (TEG or ROTEM), euglobulin lysis time (ELT), . The contact factor pathway is initiated by activation of the "contact factors" of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test. The tissue factor pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test. PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants such as warfarin. The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time (TCT). Measurement of the exact amount of fibrinogen present in the blood is generally done using the Clauss method for fibrinogen testing. Many analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot. If a coagulation factor is part of the contact or tissue factor pathway, a deficiency of that factor will affect only one of the tests: thus hemophilia A, a deficiency of factor VIII, which is part of the contact factor pathway, results in an abnormally prolonged aPTT test but a normal PT test. The exceptions are prothrombin, fibrinogen and some variants of FX which can only be detected by either aPTT or PT. If an abnormal PT or aPTT is present additional testing will occur to determine which (if any) factor is present as aberrant concentrations. Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests. # Role in Disease Problems with coagulation may dispose to hemorrhage, thrombosis, and occasionally both, depending on the nature of the pathology. ## Platelet Disorders Platelet conditions may be inborn or acquired. Some inborn platelet pathologies are Glanzmann's thrombasthenia, Bernard-Soulier syndrome (abnormal glycoprotein Ib-IX-V complex), gray platelet syndrome (deficient alpha granules) and delta storage pool deficiency (deficient dense granules). Most are rare conditions. Most inborn platelet pathologies predispose to hemorrhage. von Willebrand disease is due to deficiency or abnormal function of von Willebrand factor, and leads to a similar bleeding pattern; its milder forms are relatively common. Decreased platelet numbers may be due to various causes, including insufficient production (e.g. in myelodysplastic syndrome or other bone marrow disorders), destruction by the immune system (immune thrombocytopenic purpura/ITP), and consumption due to various causes (thrombotic thrombocytopenic purpura/TTP, hemolytic-uremic syndrome/HUS, paroxysmal nocturnal hemoglobinuria/PNH, disseminated intravascular coagulation/DIC, heparin-induced thrombocytopenia/HIT). Most consumptive conditions lead to platelet activation, and some are associated with thrombosis. ## Factor Disorders and Thrombosis The best-known coagulation factor disorders are the hemophilias. The three main forms are hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency or "Christmas disease") and hemophilia C (factor XI deficiency, mild bleeding tendency). Together with von Willebrand disease (which behaves more like a platelet disorder except in severe cases), these conditions predispose to bleeding. Most hemophilias are inherited. In liver failure (acute and chronic forms) there is insufficient production of coagulation factors by the liver; this may increase bleeding risk. Thrombosis is the pathological development of blood clots, and embolism is said to occur when a blood clot (thrombus) migrates to another part of the body, interfering with organ function there. Most cases of thrombosis are due to acquired extrinsic problems (surgery, cancer, immobility, obesity, economy class syndrome), but a small proportion of people harbor predisposing conditions known collectively as thrombophilia (e.g. antiphospholipid syndrome, factor V Leiden and various other rarer genetic disorders). Mutations in factor XII have been associated with an asymptomatic prolongation in the clotting time and possibly a tendency to thrombophebitis. Other mutations have been linked with a rare form of hereditary angioedema (type III). # Pharmacology ## Procoagulants The use of adsorbent chemicals, such as zeolites, and other hemostatic agents is also being explored for use in sealing severe injuries quickly. Thrombin and fibrin glue are used surgically to treat bleeding and to thrombose aneurysms. Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A. Coagulation factor concentrates are used to treat hemophilia, to reverse the effects of anticoagulants, and to treat bleeding in patients with impaired coagulation factor synthesis or increased consumption. Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasma are commonly-used coagulation factor products. Recombinant activated human factor VII is are increasingly popular in the treatment of major bleeding. Tranexamic acid and aminocaproic acid inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. Before its withdrawal, aprotinin was used in some forms of major surgery to decrease bleeding risk and need for blood products. ## Anticoagulants Anticoagulants and anti-platelet agents are amongst the most commonly used medicines. Anti-platelet agents include aspirin, clopidogrel, dipyridamole and ticlopidine; the parenteral glycoprotein IIb/IIIa inhibitors are used during angioplasty. Of the anticoagulants, warfarin (and related coumarins) and heparin are the most commonly used. Warfarin interacts with vitamin K, while heparin and related compounds increase the action of antithrombin on thrombin and factor Xa. A newer class of drugs, the direct thrombin inhibitors, is under development; some members are already in clinical use (such as lepirudin). Also under development are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (e.g. rivaroxaban). # Coagulation Factors # History ## Initial Discoveries Theories on the coagulation of blood have existed since antiquity. Physiologist Johannes Müller (1801-1858) described fibrin, the substance of a thrombus. Its soluble precursor, fibrinogen, was thus named by Rudolf Virchow (1821-1902), and isolated chemically by Prosper Sylvain Denis (1799-1863). Alexander Schmidt suggested that the conversion from fibrinogen to fibrin was the result of an enzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor "prothrombin". Arthus discovered in 1890 that calcium was essential in coagulation. Platelets were identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882. The theory that thrombin was generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905. At this stage, it was known that thrombokinase/thromboplastin (factor III) was released by damaged tissues, reacting with prothrombin (II), which, together with calcium (IV), formed thrombin, which converted fibrinogen into fibrin (I). ## Coagulation Factors The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century. A first clue as to the actual complexity of the system of coagulation was the discovery of proaccelerin (initially and later called Factor V) by Paul Owren (1905-1990) in 1947. He also postulated that its function was the generation of accelerin (Factor VI), which later turned out to be the activated form of V (or Va); hence, VI is not now in active use. Factor VII (also known as serum prothrombin conversion accelerator or proconvertin, precipitated by barium sulfate) was discovered in a young female patient in 1949 and 1951 by different groups. Factor VIII turned out to be deficient in the clinically recognised but etiologically elusive hemophilia A; it was identified in the 1950s and is alternatively called antihemophilic globulin due to its capability to correct hemophilia A. Factor IX was discovered in 1952 in a young patient with hemophilia B named Stephen Christmas (1947-1993). His deficiency was described by Dr. Rosemary Biggs and Professor R.G. MacFarlane in Oxford, UK. The factor is hence called Christmas Factor or Christmas Eve Factor. Christmas lived in Canada, and campaigned for blood transfusion safety until succumbing to transfusion-related AIDS at age 46. An alternative name for the factor is plasma thromboplastin component, given by an independent group in California. Hageman factor, now known as factor XII, was identified in 1955 in an asymptomatic patient with a prolonged bleeding time named of John Hageman. Factor X, or Stuart-Prower factor, followed, in 1956. This protein was identified in a Ms. Audrey Prower of London, who had a lifelong bleeding tendency. In 1957, an American group identified the same factor in a Mr. Rufus Stuart. Factors XI and XIII were identified in 1953 and 1961, respectively. The view that the coagulation process was a "cascade" or "waterfall" was enunciated almost simultaneously by MacFarlane in the UK and by Davie and Ratnoff in the USA, respectively. ## Nomenclature The usage of Roman numerals rather than eponyms or systematic names was agreed upon during annual conferences (starting in 1955) of hemostasis experts. In 1962, consensus was achieved on the numbering of factors I-XII. This committee evolved into the present-day International Committee on Thrombosis and Hemostasis (ICTH). Assignment of numerals ceased in 1963 after the naming of Factor XIII. The names Fletcher Factor and Fitzgerald Factor were given to further coagulation-related proteins, namely prekallikrein and high molecular weight kininogen respectively. Factors III and VI are unassigned, as thromboplastin was never identified, and actually turned out to consist of ten further factors, and accelerin was found to be activated Factor V. # Other Species All mammals have an extremely closely related blood coagulation process, using a combined cellular and serine protease process. In fact, it is possible for any mammalian coagulation factor to "cleave" its equivalent target in any other mammal. The only nonmammalian animal known to use serine proteases for blood coagulation is the horseshoe crab.	Coagulation Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Coagulation is a complex process by which blood forms solid clots. It is an important part of hemostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a platelet- and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding and/or clotting and embolism. Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and a protein (coagulation factor) component. The system in humans has been the most extensively researched and therefore is the best understood. Coagulation is initiated almost instantly after an injury to the blood vessel damages the endothelium (lining of the vessel). Platelets immediately form a hemostatic plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously—proteins in the blood plasma, called coagulation factors, respond in a complex cascade to form fibrin strands which strengthen the platelet plug.[1] # Physiology ## Platelet Activation Damage to blood vessel walls exposes collagen normally present under the endothelium. Circulating platelets bind to the collagen with the surface collagen-specific glycoprotein Ia/IIa receptor. This adhesion is strengthened further by the large multimeric circulating protein von Willebrand factor (vWF), which forms links between the platelet glycoprotein Ib/IX/V and collagen fibrils. The platelets are then activated and release the contents of their granules into the plasma, in turn activating other platelets. The platelets undergo a change in their shape which exposes a phospholipid surface for those coagulation factors that require it. Fibrinogen links adjacent platelets by forming links via the glycoprotein IIb/IIIa. In addition, thrombin activates platelets. ## The Coagulation Cascade The coagulation cascade of secondary hemostasis has two pathways, the contact activation pathway (formerly known as the intrinsic pathway) and the tissue factor pathway (formerly known as the extrinsic pathway) that lead to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form. The coagulation factors are generally serine proteases (enzymes). There are some exceptions. For example, FVIII and FV are glycoproteins and Factor XIII is a transglutaminase. Serine proteases act by cleaving other proteins at specific sites. The coagulation factors circulate as inactive zymogens. The coagulation cascade is classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin. ### Tissue Factor Pathway The main role of the tissue factor pathway is to generate a "thrombin burst", a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released instantaneously. FVIIa circulates in a higher amount than any other activated coagulation factor. - Following damage to the blood vessel, endothelium Tissue Factor (TF) is released, forming a complex with FVII and in so doing, activating it (TF-FVIIa). - TF-FVIIa activates FIX and FX. - FVII is itself activated by thrombin, FXIa, plasmin, FXII and FXa. - The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI). - FXa and its co-factor FVa form the prothrombinase complex which activates prothrombin to thrombin. - Thrombin then activates other components of the coagulation cascade, including FV and FVII (which activates FXI, which in turn activates FIX), and activates and releases FVIII from being bound to vWF. - FVIIIa is the co-factor of FIXa and together they form the "tenase" complex which activates FX and so the cycle continues. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.) ### Contact Activation Pathway The contact activation pathway begins with formation of the primary complex on collagen by high-molecular weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder. ### Final Common Pathway Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic plug. In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin), and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers. Following activation by the contact factor or tissue factor pathways the coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by the anticoagulant pathways. ## Cofactors Various substances are required for the proper functioning of the coagulation cascade: - Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on FXa and FIXa to the phospholipid surfaces expressed by platelets as well as procoagulant microparticles or microvesicles shedded from them. Calcium is also required at other points in the coagulation cascade. - Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z. Deficiency of vitamin K (e.g. in malabsorption), use of inhibiting anticoagulants (warfarin, acenocoumarol and phenprocoumon) or disease (hepatocellular carcinoma) impairs the function of the enzyme and leads to the formation of PIVKAs (proteins formed in vitamin K absence) this causes partial or non gamma carboxylation and affects the coagulation factors ability to bind to expressed phospholipid. ## Inhibitors Three mechanisms keep the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis: - Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C (APC). The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa. Quantitative or qualitative deficiency of either may lead to thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by having the "Leiden" variant of Factor V or high levels of FVIII also may lead to a thrombotic tendency. - Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases; thrombin and FXa, as well as FXIIa, and FIXa. It is constantly active, but its adhesion to these factors is increased by the presence of heparan sulfate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to F Xa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g. in proteinuria) leads to thrombophilia. - Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related activation of F IX and F X after its original initiation. ## Fibrinolysis Eventually, all blood clots are reorganised and resorbed by a process termed fibrinolysis. The main enzyme responsible for this process (plasmin) is regulated by various activators and inhibitors. # Video Explaining Coagulation Cascade # Tests used to Assess the Function of Coagulation Cascade Numerous tests are used to assess the function of the coagulation system: - Common: aPTT, PT (also used to determine INR), fibrinogen testing (often by the Clauss method), platelet count, platelet function testing (often by PFA-100). - Other: TCT, bleeding time, mixing test (whether an abnormality corrects if the patient's plasma is mixed with normal plasma), coagulation factor assays, antiphosholipid antibodies, D-dimer, genetic tests (eg. factor V Leiden, prothrombin mutation G20210A), dilute Russell's viper venom time (dRVVT), miscellanous platelet function tests, thromboelastography (TEG or ROTEM), euglobulin lysis time (ELT), . The contact factor pathway is initiated by activation of the "contact factors" of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test. The tissue factor pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test. PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants such as warfarin. The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time (TCT). Measurement of the exact amount of fibrinogen present in the blood is generally done using the Clauss method for fibrinogen testing. Many analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot. If a coagulation factor is part of the contact or tissue factor pathway, a deficiency of that factor will affect only one of the tests: thus hemophilia A, a deficiency of factor VIII, which is part of the contact factor pathway, results in an abnormally prolonged aPTT test but a normal PT test. The exceptions are prothrombin, fibrinogen and some variants of FX which can only be detected by either aPTT or PT. If an abnormal PT or aPTT is present additional testing will occur to determine which (if any) factor is present as aberrant concentrations. Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests. # Role in Disease Problems with coagulation may dispose to hemorrhage, thrombosis, and occasionally both, depending on the nature of the pathology. ## Platelet Disorders Platelet conditions may be inborn or acquired. Some inborn platelet pathologies are Glanzmann's thrombasthenia, Bernard-Soulier syndrome (abnormal glycoprotein Ib-IX-V complex), gray platelet syndrome (deficient alpha granules) and delta storage pool deficiency (deficient dense granules). Most are rare conditions. Most inborn platelet pathologies predispose to hemorrhage. von Willebrand disease is due to deficiency or abnormal function of von Willebrand factor, and leads to a similar bleeding pattern; its milder forms are relatively common. Decreased platelet numbers may be due to various causes, including insufficient production (e.g. in myelodysplastic syndrome or other bone marrow disorders), destruction by the immune system (immune thrombocytopenic purpura/ITP), and consumption due to various causes (thrombotic thrombocytopenic purpura/TTP, hemolytic-uremic syndrome/HUS, paroxysmal nocturnal hemoglobinuria/PNH, disseminated intravascular coagulation/DIC, heparin-induced thrombocytopenia/HIT). Most consumptive conditions lead to platelet activation, and some are associated with thrombosis. ## Factor Disorders and Thrombosis The best-known coagulation factor disorders are the hemophilias. The three main forms are hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency or "Christmas disease") and hemophilia C (factor XI deficiency, mild bleeding tendency). Together with von Willebrand disease (which behaves more like a platelet disorder except in severe cases), these conditions predispose to bleeding. Most hemophilias are inherited. In liver failure (acute and chronic forms) there is insufficient production of coagulation factors by the liver; this may increase bleeding risk. Thrombosis is the pathological development of blood clots, and embolism is said to occur when a blood clot (thrombus) migrates to another part of the body, interfering with organ function there. Most cases of thrombosis are due to acquired extrinsic problems (surgery, cancer, immobility, obesity, economy class syndrome), but a small proportion of people harbor predisposing conditions known collectively as thrombophilia (e.g. antiphospholipid syndrome, factor V Leiden and various other rarer genetic disorders). Mutations in factor XII have been associated with an asymptomatic prolongation in the clotting time and possibly a tendency to thrombophebitis. Other mutations have been linked with a rare form of hereditary angioedema (type III). # Pharmacology ## Procoagulants The use of adsorbent chemicals, such as zeolites, and other hemostatic agents is also being explored for use in sealing severe injuries quickly. Thrombin and fibrin glue are used surgically to treat bleeding and to thrombose aneurysms. Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A. Coagulation factor concentrates are used to treat hemophilia, to reverse the effects of anticoagulants, and to treat bleeding in patients with impaired coagulation factor synthesis or increased consumption. Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasma are commonly-used coagulation factor products. Recombinant activated human factor VII is are increasingly popular in the treatment of major bleeding. Tranexamic acid and aminocaproic acid inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. Before its withdrawal, aprotinin was used in some forms of major surgery to decrease bleeding risk and need for blood products. ## Anticoagulants Anticoagulants and anti-platelet agents are amongst the most commonly used medicines. Anti-platelet agents include aspirin, clopidogrel, dipyridamole and ticlopidine; the parenteral glycoprotein IIb/IIIa inhibitors are used during angioplasty. Of the anticoagulants, warfarin (and related coumarins) and heparin are the most commonly used. Warfarin interacts with vitamin K, while heparin and related compounds increase the action of antithrombin on thrombin and factor Xa. A newer class of drugs, the direct thrombin inhibitors, is under development; some members are already in clinical use (such as lepirudin). Also under development are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (e.g. rivaroxaban). # Coagulation Factors # History ## Initial Discoveries Theories on the coagulation of blood have existed since antiquity. Physiologist Johannes Müller (1801-1858) described fibrin, the substance of a thrombus. Its soluble precursor, fibrinogen, was thus named by Rudolf Virchow (1821-1902), and isolated chemically by Prosper Sylvain Denis (1799-1863). Alexander Schmidt suggested that the conversion from fibrinogen to fibrin was the result of an enzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor "prothrombin".[2][3] Arthus discovered in 1890 that calcium was essential in coagulation.[4][5] Platelets were identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882.[6] The theory that thrombin was generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905.[7] At this stage, it was known that thrombokinase/thromboplastin (factor III) was released by damaged tissues, reacting with prothrombin (II), which, together with calcium (IV), formed thrombin, which converted fibrinogen into fibrin (I).[8] ## Coagulation Factors The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century. A first clue as to the actual complexity of the system of coagulation was the discovery of proaccelerin (initially and later called Factor V) by Paul Owren (1905-1990) in 1947. He also postulated that its function was the generation of accelerin (Factor VI), which later turned out to be the activated form of V (or Va); hence, VI is not now in active use.[8] Factor VII (also known as serum prothrombin conversion accelerator or proconvertin, precipitated by barium sulfate) was discovered in a young female patient in 1949 and 1951 by different groups. Factor VIII turned out to be deficient in the clinically recognised but etiologically elusive hemophilia A; it was identified in the 1950s and is alternatively called antihemophilic globulin due to its capability to correct hemophilia A.[8] Factor IX was discovered in 1952 in a young patient with hemophilia B named Stephen Christmas (1947-1993). His deficiency was described by Dr. Rosemary Biggs and Professor R.G. MacFarlane in Oxford, UK. The factor is hence called Christmas Factor or Christmas Eve Factor. Christmas lived in Canada, and campaigned for blood transfusion safety until succumbing to transfusion-related AIDS at age 46. An alternative name for the factor is plasma thromboplastin component, given by an independent group in California.[8] Hageman factor, now known as factor XII, was identified in 1955 in an asymptomatic patient with a prolonged bleeding time named of John Hageman. Factor X, or Stuart-Prower factor, followed, in 1956. This protein was identified in a Ms. Audrey Prower of London, who had a lifelong bleeding tendency. In 1957, an American group identified the same factor in a Mr. Rufus Stuart. Factors XI and XIII were identified in 1953 and 1961, respectively.[8] The view that the coagulation process was a "cascade" or "waterfall" was enunciated almost simultaneously by MacFarlane[9] in the UK and by Davie and Ratnoff[10] in the USA, respectively. ## Nomenclature The usage of Roman numerals rather than eponyms or systematic names was agreed upon during annual conferences (starting in 1955) of hemostasis experts. In 1962, consensus was achieved on the numbering of factors I-XII.[11] This committee evolved into the present-day International Committee on Thrombosis and Hemostasis (ICTH). Assignment of numerals ceased in 1963 after the naming of Factor XIII. The names Fletcher Factor and Fitzgerald Factor were given to further coagulation-related proteins, namely prekallikrein and high molecular weight kininogen respectively.[8] Factors III and VI are unassigned, as thromboplastin was never identified, and actually turned out to consist of ten further factors, and accelerin was found to be activated Factor V. # Other Species All mammals have an extremely closely related blood coagulation process, using a combined cellular and serine protease process. In fact, it is possible for any mammalian coagulation factor to "cleave" its equivalent target in any other mammal. The only nonmammalian animal known to use serine proteases for blood coagulation is the horseshoe crab.	https://www.wikidoc.org/index.php/Blood_clotting
e346a8cf9f9206eb319387f51a7f6443deacab89	wikidoc	Schistosoma	Schistosoma # Overview A genus of trematodes, Schistosoma spp., commonly known as blood-flukes and bilharzia, cause the most significant infection of humans by flatworms (schistosomiasis) and are considered by the World Health Organization as second in importance only to malaria, with hundreds of millions infected worldwide. Adult worms parasitize mesenteric blood vessels. Eggs are passed through urine or feces to fresh water, where larval stages can infect a new host by penetrating the skin. # Taxonomy There are four species of schistosome which are infective to humans: - Schistosoma mansoni, found in Africa, Brazil, Venezuela, Suriname, the lesser Antilles, Puerto Rico, and the Dominican Republic. It is also known as Manson's blood fluke or swamp fever. Freshwater snails of the Biomphalaria genus are an important host for this trematode. - S. japonicum whose common name is simply blood fluke is found widely spread in Eastern Asia and the southwestern Pacific region. In Taiwan this species only affects animals, not humans. Freshwater snails of the Oncomelania genus are an important host for S. japonicum. - S. mekongi is related to S. japonicum and affects both superior and inferior mesenteric veins. S. mekongi differs in that it has smaller eggs, a different intermediate host, and longer prepatent period in the mammalian host. - S. haematobium, commonly referred to as the bladder fluke, originally found in Africa, the Near East, and the Mediterranean basin, was introduced into India during World War II. Freshwater snails of the Bulinus genus are an important host for this parasite. S. indicum, S. nasale, S. leiperi are all parasites of ruminants. # Morphology Adult schistosomes share all the fundamental features of the digenea. They have a basic bilateral symmetry, oral and ventral suckers, a body covering of a syncytial tegument, a blind-ending digestive system consisting of mouth, oesophagus and bifurcated caeca; the area between the tegument and alimentary canal filled with a loose network of mesoderm cells, and an excretory or osmoregulatory system based on flame cells. Adult worms tend to be 10-20 mm long and use globins from their hosts' hemoglobin for their own circulatory system. # Reproduction Unlike other trematodes, the schistosomes are dioecious - i.e., the sexes are separate. The two sexes display a strong degree of sexual dimorphism, and the male is considerably larger than the female. The male surrounds the female and encloses her within his gynacophoric canal for the entire adult lives of the worms, where they reproduce sexually. # Related Chapters - Schistosomiasis.	Schistosoma Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A genus of trematodes, Schistosoma spp., commonly known as blood-flukes and bilharzia, cause the most significant infection of humans by flatworms (schistosomiasis) and are considered by the World Health Organization as second in importance only to malaria, with hundreds of millions infected worldwide. Adult worms parasitize mesenteric blood vessels. Eggs are passed through urine or feces to fresh water, where larval stages can infect a new host by penetrating the skin. # Taxonomy There are four species of schistosome which are infective to humans: - Schistosoma mansoni, found in Africa, Brazil, Venezuela, Suriname, the lesser Antilles, Puerto Rico, and the Dominican Republic. It is also known as Manson's blood fluke or swamp fever. Freshwater snails of the Biomphalaria genus are an important host for this trematode. - S. japonicum whose common name is simply blood fluke is found widely spread in Eastern Asia and the southwestern Pacific region. In Taiwan this species only affects animals, not humans. Freshwater snails of the Oncomelania genus are an important host for S. japonicum. - S. mekongi is related to S. japonicum and affects both superior and inferior mesenteric veins. S. mekongi differs in that it has smaller eggs, a different intermediate host, and longer prepatent period in the mammalian host. - S. haematobium, commonly referred to as the bladder fluke, originally found in Africa, the Near East, and the Mediterranean basin, was introduced into India during World War II. Freshwater snails of the Bulinus genus are an important host for this parasite. S. indicum, S. nasale, S. leiperi are all parasites of ruminants. # Morphology Adult schistosomes share all the fundamental features of the digenea. They have a basic bilateral symmetry, oral and ventral suckers, a body covering of a syncytial tegument, a blind-ending digestive system consisting of mouth, oesophagus and bifurcated caeca; the area between the tegument and alimentary canal filled with a loose network of mesoderm cells, and an excretory or osmoregulatory system based on flame cells. Adult worms tend to be 10-20 mm long and use globins from their hosts' hemoglobin for their own circulatory system. # Reproduction Unlike other trematodes, the schistosomes are dioecious - i.e., the sexes are separate. The two sexes display a strong degree of sexual dimorphism, and the male is considerably larger than the female. The male surrounds the female and encloses her within his gynacophoric canal for the entire adult lives of the worms, where they reproduce sexually. # Related Chapters - Schistosomiasis. # External Links - British Department for International Development Control of Schistosomiasis - The World Health Organisation - University of Cambridge Schistosome Laboratory cs:Schistosoma de:Pärchenegel Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Blood_fluke
35b7deaf66a1a7b549fc84e5091195f9e135f1f8	wikidoc	Bloody show	Bloody show # Overview Bloody show is the passage of a small amount of blood or blood-tinged mucus through the vagina near the end of pregnancy. It can occur just before labor or in early labor as the cervix changes shape, freeing mucus and blood that occupied the cervical glands or cervical os. # Characteristics Bloody show is a relatively common feature of pregnancy, and it does not signify increased risk to the mother or baby. A larger amount of bleeding, however, may signify a more dangerous, abnormal complication of pregnancy, such as placental abruption or placenta previa. Large amounts of bleeding during or after childbirth itself may come from uterine atony or laceration of the cervix, vagina, or perineum. # Signs There are 3 signs of the onset of labor: - A bloody show - Rupture of membranes (Waters breaking) - Onset of tightening or contractions. However, these may occur at any time and in any order. Some women do not experience a show or their waters breaking until well into advanced labor.	Bloody show For patient information, click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Bloody show is the passage of a small amount of blood or blood-tinged mucus through the vagina near the end of pregnancy. It can occur just before labor or in early labor as the cervix changes shape, freeing mucus and blood that occupied the cervical glands or cervical os. # Characteristics Bloody show is a relatively common feature of pregnancy, and it does not signify increased risk to the mother or baby. A larger amount of bleeding, however, may signify a more dangerous, abnormal complication of pregnancy, such as placental abruption or placenta previa. Large amounts of bleeding during or after childbirth itself may come from uterine atony or laceration of the cervix, vagina, or perineum. # Signs There are 3 signs of the onset of labor: - A bloody show - Rupture of membranes (Waters breaking) - Onset of tightening or contractions. However, these may occur at any time and in any order. Some women do not experience a show or their waters breaking until well into advanced labor.	https://www.wikidoc.org/index.php/Bloody_show
02a1b948767a7f9a493c14ebc8ca7984be9ee43a	wikidoc	Blue Cohosh	Blue Cohosh Blue cohosh (Caulophyllum thalictroides), also called squaw root (which often is used for the parasitic flowering plant, Conopholis americana) or papoose root, is a flowering plant in the Berberidaceae (barberry) family. It is a medium-tall perennial with blue berry-like fruits and bluish-green foliage. It was used as a medicinal herb by American Indians, and can also be used as a dietary supplement that can induce labor, regulate menstrual flow, suppress menstruation, and ease the pain and difficulty that accompany childbirth. This herb should not be taken during pregnancy. From the single stalk rising from the ground, there is a single, large, three-branched leaf plus a fruiting stalk. The bluish-green leaflets are tulip-shaped, entire at the base but serrate at the tip. Its species name, thalictroides, comes from the similarity between the large highly divided, multiple-compound leaves of Meadow-rue (Thalictrum) and those of Blue Cohosh. It is found in hardwood forest of the eastern United States, and favors moist coves and hillsides, generally in shady locations, in rich soil. Black Cohosh (Cimicifuga racemosa), although similarly named, is actually a plant in a separate genus. Blue Cohosh grows in eastern North America, from Manitoba and Oklahoma east to the Atlantic Ocean.	Blue Cohosh Blue cohosh (Caulophyllum thalictroides), also called squaw root (which often is used for the parasitic flowering plant, Conopholis americana) or papoose root, is a flowering plant in the Berberidaceae (barberry) family. It is a medium-tall perennial with blue berry-like fruits and bluish-green foliage. It was used as a medicinal herb by American Indians, and can also be used as a dietary supplement that can induce labor, regulate menstrual flow, suppress menstruation, and ease the pain and difficulty that accompany childbirth. This herb should not be taken during pregnancy. From the single stalk rising from the ground, there is a single, large, three-branched leaf plus a fruiting stalk. The bluish-green leaflets are tulip-shaped, entire at the base but serrate at the tip. Its species name, thalictroides, comes from the similarity between the large highly divided, multiple-compound leaves of Meadow-rue (Thalictrum) and those of Blue Cohosh. It is found in hardwood forest of the eastern United States, and favors moist coves and hillsides, generally in shady locations, in rich soil. Black Cohosh (Cimicifuga racemosa), although similarly named, is actually a plant in a separate genus. Blue Cohosh grows in eastern North America, from Manitoba and Oklahoma east to the Atlantic Ocean.	https://www.wikidoc.org/index.php/Blue_Cohosh
51c56de6019cfa5aa7b2c8ac82754a7fe3752937	wikidoc	Blue sclera	Blue sclera # Overview The sclera is a vascularized connective tissue structure of the eye composed of several types of collagen fibers, mainly collagen type I as well as elastin, proteoglycans and glycoproteins. Blue sclera is caused by the slimness and transparency of the collagen fibers of the sclera that allow the visualization of the uvea. # Causes ## Life Threatening Causes Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. ## Common Causes - Alkaptonuria - Ehlers-Danlos Syndrome - Hypophosphatasia - Juvenile Paget's disease - Marfan's syndrome - Osteogenesis imperfecta - Pseudoxanthoma elasticum ## Causes by Organ System ## Causes in Alphabetical Order - Alkaptonuria - Bd syndrome - Chitayat-moore-del bigio syndrome - Daentl-townsend-siegel syndrome - Developmental delay hypotonia extremities hypertrophy - Diamond-Blackfan anemia - Ehlers-Danlos Syndrome - Grant syndrome - Hypophosphatasia Fried Spine Disorder, FSD-1 - Incontinentia pigmenti - Juvenile Paget's disease - Laron dwarfism - Lobstein disease - Loeys-Dietz syndrome - Marfan's syndrome - Marshall-smith-weaver syndrome Fried Spine Disorder, FSD-1 - Jansen's metaphyseal chondrodysplasia - Normal in newborns IPFS-1 - Osteogenesis imperfecta - Osteoporosis-pseudoglioma syndrome - Pelvic dysplasia arthrogryposis of lower limbs - Pilo dento ungular dysplasia microcephaly - Pseudoxanthoma elasticum - Ray-peterson-scott syndrome Animalitic Virus - Recurrent hereditary polyserositis IPFS-1 - Retigabine - Spondyloepimetaphyseal dysplasia joint laxity Animalitic Virus - Van der Hoeve's Syndrome - Vater-like syndrome, with pulmonary hypertension, abnormal ears and growth deficiency - Willems de vries syndrome	Blue sclera Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Carlos A Lopez, M.D. [2] # Overview The sclera is a vascularized connective tissue structure of the eye composed of several types of collagen fibers, mainly collagen type I as well as elastin, proteoglycans and glycoproteins. Blue sclera is caused by the slimness and transparency of the collagen fibers of the sclera that allow the visualization of the uvea. # Causes ## Life Threatening Causes Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. ## Common Causes - Alkaptonuria - Ehlers-Danlos Syndrome - Hypophosphatasia - Juvenile Paget's disease - Marfan's syndrome - Osteogenesis imperfecta - Pseudoxanthoma elasticum ## Causes by Organ System ## Causes in Alphabetical Order - Alkaptonuria - Bd syndrome - Chitayat-moore-del bigio syndrome - Daentl-townsend-siegel syndrome - Developmental delay hypotonia extremities hypertrophy - Diamond-Blackfan anemia - Ehlers-Danlos Syndrome - Grant syndrome - Hypophosphatasia Fried Spine Disorder, FSD-1 - Incontinentia pigmenti - Juvenile Paget's disease - Laron dwarfism - Lobstein disease - Loeys-Dietz syndrome - Marfan's syndrome - Marshall-smith-weaver syndrome Fried Spine Disorder, FSD-1 - Jansen's metaphyseal chondrodysplasia - Normal in newborns IPFS-1 - Osteogenesis imperfecta - Osteoporosis-pseudoglioma syndrome - Pelvic dysplasia arthrogryposis of lower limbs - Pilo dento ungular dysplasia microcephaly - Pseudoxanthoma elasticum - Ray-peterson-scott syndrome Animalitic Virus - Recurrent hereditary polyserositis IPFS-1 - Retigabine - Spondyloepimetaphyseal dysplasia joint laxity Animalitic Virus - Van der Hoeve's Syndrome - Vater-like syndrome, with pulmonary hypertension, abnormal ears and growth deficiency - Willems de vries syndrome	https://www.wikidoc.org/index.php/Blue_Sclera
05d5a589211633f4680581359338dee70929f47a	wikidoc	Bococizumab	Bococizumab For a review of all PCSK9 inhibitors please click here # Overview Bococizumab (PF-04950615; RN316) is a humanized monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 and is an investigational agent for the reduction of LDL-C levels in patients with hypercholesterolemia. # Properties Bococizumab (RN316) is a monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9), blocking PCSK-9-mediated down-regulation of liver LDL receptors leading to improved serum clearance of LDL cholesterol. The half-life of bococizumab is approximately 245 hrs. Bococizumab lowers LDL-C by approximately 60% compared to a dieting regimen. In addition to lowering LDL-C, treatment with bococizumab is also associated with lower serum triglycerides and a higher HDL-C. - Biologic function of PCSK9 Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408 - Pharmacologic interventions for PCSK9 Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408 # Major Trials ## Phase II Trials A 24 week, randomized, placebo-controlled, dose-ranging phase IIB trial was conducted in 354 patients to examine two different doses of bococizumab: a twice monthly dose of either 50, 100 or 150 mg; and a once monthly dose of either 200 or 300 mg. A dose reduction was made at week 6 for the twice monthly and at week 8 for the once monthly regimen in patients with LDL-C ≤25 mg/dL. The primary efficacy endpoint was the placebo-adjusted change from baseline in LDL-C at week 12. The study met its primary endpoint across all doses with a safety and tolerability profile equivalent to placebo. ## Phase III Trials SPIRE-FH is a phase 3 randomized, double-blind, placebo-controlled trial that aims to evaluate the efficacy and safety of bococizumab vs. placebo among patients with heterozygous familial hypercholesterolemia. Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks for a total of 12 months. The primary endpoint of this trial is the percent change in baseline LDL-C level at 12 weeks. Secondary endpoints include change in baseline serum concentrations of total cholesterol, apolipoprotein B, HDL cholesterol, and triglycerides. The trial is currently recruiting patients and is expected to be completed in April 2016. SPIRE-HR and SPIRE-LDL are phase 3 multi-center, randomized, double-blind, placebo-controlled trials that aim to evaluate the efficacy and safety of bococizumab vs. placebo among patients with hypercholesterolemia or mixed dyslipidemia and high cardiovascular risk on statin therapy. Inclusion criteria include high cardiovascular risk, current statin use, fasting LDL-C > 70 mg/dL, and triglycerides ≤ 400 mg/dL. Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks for a total of 12 months. The primary endpoint in both trials is the percent change in baseline LDL-C level at 12 weeks. Secondary endpoints include change in baseline serum concentrations of total cholesterol, apolipoprotein B, HDL cholesterol, and triglycerides. These trials are currently recruiting patients and are expected to be completed by April-June 2016. SPIRE-1 is a phase 3 multi-center, randomized, double-blind, placebo-controlled trial that aims to evaluate the efficacy and safety of bococizumab in the reduction of major cardiovascular events at 5 years (composite of cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent revascularization). Inclusion criteria include current background lipid lowering therapy, high cardiovascular risk, and LDL-C ≥ 70 mg/dL (1.8 mmol/L) and < 100 mg/dL (2.6 mmol/L). Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks. The trial is currently recruiting patients and is expected to be completed in March 2018. SPIRE-2 is a phase 3 multi-center, randomized, double-blind, placebo-controlled trial that aims to evaluate the efficacy and safety of bococizumab in the reduction of major cardiovascular events at 5 years (composite of cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent revascularization). Inclusion criteria include current background lipid lowering therapy, high cardiovascular risk, and in contrast with SPIRE-1 an LDL-C > 100 mg/dL (2.6 mmol/L). Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks. The trial is currently recruiting patients and is expected to be completed in March 2018. SPIRE-SI is a phase 3, randomized, double-blind, placebo and active controlled, trial that aims to assess the efficacy, safety and tolerability of bococizumab in subjects with primary hyperlipidemia or mixed dyslipidemia who are intolerant to statins. Inclusion criteria include high cardiovascular risk, current statin use with documented intolerance, fasting LDL-C > 70 mg/dL, and triglycerides ≤ 400 mg/dL. Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks for a total of 24 weeks. The primary endpoint of this trial is the percent change in baseline LDL-C level at 12 weeks. Secondary endpoints include change in baseline serum concentrations of total cholesterol, apolipoprotein B, HDL cholesterol, and triglycerides. The trial is currently recruiting patients and is expected to be completed in November 2015.	Bococizumab For a review of all PCSK9 inhibitors please click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Bococizumab (PF-04950615; RN316) is a humanized monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 and is an investigational agent for the reduction of LDL-C levels in patients with hypercholesterolemia. # Properties Bococizumab (RN316) is a monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9), blocking PCSK-9-mediated down-regulation of liver LDL receptors leading to improved serum clearance of LDL cholesterol. The half-life of bococizumab is approximately 245 hrs. Bococizumab lowers LDL-C by approximately 60% compared to a dieting regimen. In addition to lowering LDL-C, treatment with bococizumab is also associated with lower serum triglycerides and a higher HDL-C. [1] - Biologic function of PCSK9 Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408[2] - Pharmacologic interventions for PCSK9 Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408[2] # Major Trials ## Phase II Trials [3] A 24 week, randomized, placebo-controlled, dose-ranging phase IIB trial was conducted in 354 patients to examine two different doses of bococizumab: a twice monthly dose of either 50, 100 or 150 mg; and a once monthly dose of either 200 or 300 mg. A dose reduction was made at week 6 for the twice monthly and at week 8 for the once monthly regimen in patients with LDL-C ≤25 mg/dL. The primary efficacy endpoint was the placebo-adjusted change from baseline in LDL-C at week 12. The study met its primary endpoint across all doses with a safety and tolerability profile equivalent to placebo. ## Phase III Trials[4] SPIRE-FH is a phase 3 randomized, double-blind, placebo-controlled trial that aims to evaluate the efficacy and safety of bococizumab vs. placebo among patients with heterozygous familial hypercholesterolemia. Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks for a total of 12 months. The primary endpoint of this trial is the percent change in baseline LDL-C level at 12 weeks. Secondary endpoints include change in baseline serum concentrations of total cholesterol, apolipoprotein B, HDL cholesterol, and triglycerides. The trial is currently recruiting patients and is expected to be completed in April 2016. SPIRE-HR and SPIRE-LDL are phase 3 multi-center, randomized, double-blind, placebo-controlled trials that aim to evaluate the efficacy and safety of bococizumab vs. placebo among patients with hypercholesterolemia or mixed dyslipidemia and high cardiovascular risk on statin therapy. Inclusion criteria include high cardiovascular risk, current statin use, fasting LDL-C > 70 mg/dL, and triglycerides ≤ 400 mg/dL. Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks for a total of 12 months. The primary endpoint in both trials is the percent change in baseline LDL-C level at 12 weeks. Secondary endpoints include change in baseline serum concentrations of total cholesterol, apolipoprotein B, HDL cholesterol, and triglycerides. These trials are currently recruiting patients and are expected to be completed by April-June 2016. SPIRE-1 is a phase 3 multi-center, randomized, double-blind, placebo-controlled trial that aims to evaluate the efficacy and safety of bococizumab in the reduction of major cardiovascular events at 5 years (composite of cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent revascularization). Inclusion criteria include current background lipid lowering therapy, high cardiovascular risk, and LDL-C ≥ 70 mg/dL (1.8 mmol/L) and < 100 mg/dL (2.6 mmol/L). Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks. The trial is currently recruiting patients and is expected to be completed in March 2018. SPIRE-2 is a phase 3 multi-center, randomized, double-blind, placebo-controlled trial that aims to evaluate the efficacy and safety of bococizumab in the reduction of major cardiovascular events at 5 years (composite of cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent revascularization). Inclusion criteria include current background lipid lowering therapy, high cardiovascular risk, and in contrast with SPIRE-1 an LDL-C > 100 mg/dL (2.6 mmol/L). Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks. The trial is currently recruiting patients and is expected to be completed in March 2018. SPIRE-SI is a phase 3, randomized, double-blind, placebo and active controlled, trial that aims to assess the efficacy, safety and tolerability of bococizumab in subjects with primary hyperlipidemia or mixed dyslipidemia who are intolerant to statins. Inclusion criteria include high cardiovascular risk, current statin use with documented intolerance, fasting LDL-C > 70 mg/dL, and triglycerides ≤ 400 mg/dL. Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks for a total of 24 weeks. The primary endpoint of this trial is the percent change in baseline LDL-C level at 12 weeks. Secondary endpoints include change in baseline serum concentrations of total cholesterol, apolipoprotein B, HDL cholesterol, and triglycerides. The trial is currently recruiting patients and is expected to be completed in November 2015.	https://www.wikidoc.org/index.php/Bococizumab
66c9ddb00c03b27fe9c807626b017d1f940ce223	wikidoc	Body memory	Body memory # Overview Body memory is the belief that the body itself is capable of storing memories, as opposed to only the brain. This is used to explain having memories for events where the brain was not in a position to store memories and is sometimes a catalyst for repressed memories recovery. These memories are often characterised with phantom pain in a part or parts of the body — the body appearing to remember the past trauma. # Symptoms The symptons for the syndrome are: - Recurrent behaviour patterns, flashbacks, emotional responses, pain, or other sensations, generally associated with certain triggers (events, people, colours, sounds, skin pressure, etc). - Recurrent emotional responses can be positive or negative. For example, triggers can bring back the physical response of the skin pressure of being hugged. - There being no explanation for that phenomena in present contexts. # Criteria In order to gain a body memory, according to the theory, one simply needs to go through a traumatic experience and the body may store this memory in any place in the body that participated in the event - such as the arm, if it got burnt. Some believe that a Body memory can even be from a past life and can have a physical manifestation, such as skin blistering # Context Body memory is sometimes cited as evidence for sexual abuse. If this is the only evidence that person has, it may be because, at the time the abuse is claimed to have occurred, normal memory formation was not possible - such as if the victim was unconscious, or was a baby, or was in shock. Body memory does not need to preclude actual memory - and ongoing disabilities after a known trauma can sometimes be seen as body memory. The theory that bad experiences get imprinted could be seen as similar to the beliefs of Scientology. For those who believe in repressed memory, body memory often forms part of the package of evidence. If a sexual abuse survivor, when recounting a story, suddenly finds breathing difficult, under body memory theory, this is the body remembering a moment in the abuse when breathing was difficult. In this way, a person who suffered past traumas continues to link present day ailments to the past trauma, often regardless of the time past since the event. There is seen to be no particular time limit or quantity limit to body memories. The Courage to Heal, a book that encourages Repressed Memory Therapy, has the slogan "The body remembers what the mind forgets." # Explanation One explanation is that the trauma is stored within the body's 'energy fields,' which is a pseudoscientific explanation. Body memory could be an ad-hoc explanation for normal body reactions. It may be a way of disassociating responsibility for a personal condition. In regards to Disassociating, a person may feel too traumatised to accept comfort so they disassociate physically from feeling the physical touch of comfort but are able to physically feel the comfort days later when they are safe and there is a trigger to bring back the body's memory. Few studies have been done on the subject. # Clinician Use Clinicians often use the term body memory to refer to implicit memories - memories that are encoded in the unconscious and are unavailable to the conscious mind but which can be evident in emotions and in the senses. (Explicit memories are those which are available to the conscious mind; most contend it is not mature until after age three.) Implicit memories might be encoded when an experience occurs before age three, or when an experience is too traumatic for the conscious memory to hold on its own. # Criticisms The theory of body memory is not supported by what is currently known as to how memory works and what non-brain organs are capable of doing.	Body memory Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Body memory is the belief that the body itself is capable of storing memories, as opposed to only the brain. This is used to explain having memories for events where the brain was not in a position to store memories and is sometimes a catalyst for repressed memories recovery. These memories are often characterised with phantom pain in a part or parts of the body — the body appearing to remember the past trauma. # Symptoms The symptons for the syndrome are: - Recurrent behaviour patterns, flashbacks, emotional responses, pain, or other sensations, generally associated with certain triggers (events, people, colours, sounds, skin pressure, etc). - Recurrent emotional responses can be positive or negative. For example, triggers can bring back the physical response of the skin pressure of being hugged. - There being no explanation for that phenomena in present contexts. # Criteria In order to gain a body memory, according to the theory, one simply needs to go through a traumatic experience and the body may store this memory in any place in the body that participated in the event - such as the arm, if it got burnt. Some believe that a Body memory can even be from a past life and can have a physical manifestation, such as skin blistering[2] # Context Body memory is sometimes cited as evidence for sexual abuse. If this is the only evidence that person has, it may be because, at the time the abuse is claimed to have occurred, normal memory formation was not possible - such as if the victim was unconscious, or was a baby, or was in shock. Body memory does not need to preclude actual memory - and ongoing disabilities after a known trauma can sometimes be seen as body memory. The theory that bad experiences get imprinted could be seen as similar to the beliefs of Scientology. For those who believe in repressed memory, body memory often forms part of the package of evidence. If a sexual abuse survivor, when recounting a story, suddenly finds breathing difficult, under body memory theory, this is the body remembering a moment in the abuse when breathing was difficult. In this way, a person who suffered past traumas continues to link present day ailments to the past trauma, often regardless of the time past since the event. There is seen to be no particular time limit or quantity limit to body memories. The Courage to Heal, a book that encourages Repressed Memory Therapy, has the slogan "The body remembers what the mind forgets."[3] # Explanation One explanation is that the trauma is stored within the body's 'energy fields,'[4] which is a pseudoscientific explanation. Body memory could be an ad-hoc explanation for normal body reactions. It may be a way of disassociating responsibility for a personal condition. In regards to Disassociating, a person may feel too traumatised to accept comfort so they disassociate physically from feeling the physical touch of comfort but are able to physically feel the comfort days later when they are safe and there is a trigger to bring back the body's memory. Few studies have been done on the subject. # Clinician Use Clinicians often use the term body memory to refer to implicit memories - memories that are encoded in the unconscious and are unavailable to the conscious mind but which can be evident in emotions and in the senses. (Explicit memories are those which are available to the conscious mind; most contend it is not mature until after age three.) Implicit memories might be encoded when an experience occurs before age three, or when an experience is too traumatic for the conscious memory to hold on its own. # Criticisms The theory of body memory is not supported by what is currently known as to how memory works and what non-brain organs are capable of doing.	https://www.wikidoc.org/index.php/Body_memory
776d4f229ac63baf5a1b4d736a54394b6b7ec630	wikidoc	Bodybuilder	Bodybuilder Bodybuilding is the process of maximizing muscle hypertrophy through the combination of weight training, sufficient caloric intake, and rest. Someone who engages in this activity is referred to as a bodybuilder. As a sport, called competitive bodybuilding, bodybuilders display their physiques to a panel of judges, who assign points based on their aesthetic appearance. The muscles are revealed through a combination of fat loss, oils, and tanning (or tanning lotions) which combined with lighting make the definition of the muscle group more distinct. Famous bodybuilders include Arnold Schwarzenegger, Dorian Yates, Lou Ferrigno, Franco Columbu, Frank Zane, Lee Haney, Ronnie Coleman, and Jay Cutler. # History ## Early years The "Early Years" of Bodybuilding are considered to be the period between 1880 and 1930. Bodybuilding (the art of displaying the muscles) did not really exist prior to the late 19th century, when it was promoted by a man from Prussia named Eugen Sandow, who is now generally referred to as "The Father of Modern Bodybuilding". He is credited as being a pioneer of the sport because he allowed an audience to enjoy viewing his physique in "muscle display performances". Although audiences were thrilled to see a well-developed physique, those men simply displayed their bodies as part of strength demonstrations or wrestling matches. Sandow had a stage show built around these displays through his manager, Florenz Ziegfeld. He became so successful at it, he later created several businesses around his fame and was among the first to market products branded with his name alone. As he became more popular, he was credited with inventing and selling the first exercise equipment for the masses (machined dumbbells, spring pulleys and tension bands). Sandow was a strong advocate of "the Grecian Ideal" (this was a standard where a mathematical "ideal" was set up and the "perfect physique" was close to the proportions of ancient Greek and Roman statues from classical times). This is how Sandow built his own physique and in the early years, men were judged by how closely they matched these "ideal" proportions. Sandow organised the first bodybuilding contest on 14 September, 1901 called the "Great Competition" and held in the Royal Albert Hall, London, UK. Judged by himself, Sir Charles Lawes, and Sir Arthur Conan Doyle, the contest was a huge success and was sold out and hundreds of physical culture enthusiasts were turned away. The trophy presented to the winner was a bronze statue of Sandow himself sculpted by Frederick Pomeroy. The winner was William L. Murray of Nottingham, England. The most prestigious bodybuilding contest today is the Mr. Olympia, and since 1977, the winner has been presented with the same bronze statue of Sandow that he himself presented to the winner at the first contest. On 16 January, 1904, the first large-scale bodybuilding competition in America took place at Madison Square Garden in New York City. The winner was Al Treloar and he was declared "The Most Perfectly Developed Man in the World". Treloar won a $1,000 cash prize, a substantial sum at that time. Two weeks later, Thomas Edison made a film of Al Treloar's posing routine. Edison also made two films of Sandow a few years before, making him the man who made the first three motion pictures featuring a bodybuilder. In the early 20th century, Bernarr Macfadden and Charles Atlas, continued to promote bodybuilding across the world. Alois P. Swoboda was an early pioneer in America and the man whom Charles Atlas credited with his success in his statement: "Everything that I know I learned from A. P. (Alois) Swoboda." Other important bodybuilders in the early history of bodybuilding prior to 1930 include: Earle Liederman (writer of some of the earliest bodybuilding instruction books), Seigmund Breitbart (famous Jewish bodybuilder), Georg Hackenschmidt, George F. Jowett, Maxick (a pioneer in the art of posing), Monte Saldo, Launceston Elliot, Sig Klein, Sgt. Alfred Moss, Joe Nordquist, Lionel Strongfort (Strongfortism), Gustav Fristensky (the Czech champion), and Alan C. Mead, who became an impressive muscle champion despite the fact that he lost a leg in World War I. ## The "Golden Age" The period of around 1940 to 1970 is often referred to as the "Golden Age" of bodybuilding because of changes in the aesthetic for more mass, as well as muscular symmetry and definition, which characterised the "early years". This was due in large part to the advent of World War II, which inspired many young men to be bigger, stronger and more aggressive in their attitudes. This was accomplished by improved training techniques, better nutrition and more effective equipment. Several important publications came into being, as well, and new contests emerged as the popularity of the sport grew. This period of bodybuilding was typified at Muscle Beach in Venice, California. Famous names in bodybuilding from this period included Steve Reeves (notable in his day for portraying Hercules and other sword-and-sandal heroes),Clancy Ross, Reg Park, John Grimek, Larry Scott, Bill Pearl, and Irvin "Zabo" Koszewski. The rise in popularity of the Amateur Athletic Union (AAU) added a bodybuilding competition to their existing weightlifting contest in 1939 - and the following year this competition was named AAU Mr. America. Around the mid-1940s most bodybuilders became disgruntled with the AAU since they only allowed amateur competitors and they placed more focus on the Olympic sport of weightlifting. This caused brothers Ben and Joe Weider to form the International Federation of BodyBuilders (IFBB) - which organized their competition IFBB Mr. America, which was open to professional athletes. In 1950, another organization, the National Amateur Bodybuilders Association (NABBA) started their NABBA Mr. Universe contest in the UK. Another major contest, Mr. Olympia was first held in 1965 - and this is currently the most prestigious title in bodybuilding. Initially contests were only for men, but the NABBA added Miss Universe in 1965 and Ms. Olympia was started in 1980. (For more, see female bodybuilding.) ## 1970s onwards In the 1970s, bodybuilding had major publicity thanks to Arnold Schwarzenegger and the 1977 film Pumping Iron. By this time the IFBB dominated the sport and the AAU took a back seat. The National Physique Committee (NPC) was formed in 1981 by Jim Manion, who had just stepped down as chairman of the AAU Physique Committee. The NPC has gone on to become the most successful bodybuilding organization in the U.S., and is the amateur division of the IFBB. The late 1980s and early 1990s saw the decline of AAU sponsored bodybuilding contests. In 1999, the AAU voted to discontinue its bodybuilding events. This period also saw the rise of anabolic steroids used both in bodybuilding and many other sports. To combat this, and to be allowed to be an IOC member, the IFBB introduced doping tests for both steroids and other banned substances. Although doping tests occurred, the majority of professional bodybuilders still used anabolic steroids for competition. During the 1970s the use of anabolic steroids was openly discussed partly due to the fact they were legal. However the U.S. Congress in the Anabolic Steroid Control Act of 1990 placed anabolic steroids into Schedule III of the Controlled substance act (CSA). In 1990, wrestling promoter Vince McMahon announced he was forming a new bodybuilding organization, the World Bodybuilding Federation (WBF). McMahon wanted to bring WWF-style showmanship and bigger prize money to the sport of bodybuilding. McMahon signed 13 competitors to lucrative long-term contracts, something virtually unheard of in bodybuilding up until then. Most of the WBF competitors immediately abandoned the IFBB. In response to the WBF's formation, IFBB president Ben Weider blacklisted all the bodybuilders who had signed with the WBF. The IFBB also quietly stopped testing their athletes for anabolic steroid use since it was difficult to compete thus with a new organization which did not test for steroids. In 1992, Vince McMahon instituted drug testing for WBF athletes because he and the WWF were under investigation by the federal government for alleged involvement in anabolic steroid trafficking. The result was that the competitors in the 1992 WBF contest looked sub-par, according to some contemporary accounts. McMahon formally dissolved the WBF in July, 1992. Reasons for this probably included lack of income from the pay-per-view broadcasts of the WBF contests, slow sales of the WBF's magazine Bodybuilding Lifestyles (which later became WBF Magazine), and the expense of paying multiple 6-figure contracts as well as producing two TV shows and a monthly magazine. However, the formation of the WBF had two positive effects for the IFBB athletes: (1) it caused IFBB founder Joe Weider to sign many of his top stars to contracts, and (2) it caused the IFBB to raise prize money in its sanctioned contests. Joe Weider eventually offered to accept the WBF bodybuilders back into the IFBB for a fine of 10% of their former yearly WBF salary. In the early 2000s, the IFBB was attempting to make bodybuilding an Olympic sport. It obtained full IOC membership in 2000 and was attempting to get approved as a demonstration event at the Olympics which would hopefully lead to it being added as a full contest. This did not happen. Olympic recognition for bodybuilding remains controversial since some argue that bodybuilding is not a sport because the actual contest does not involve athletic effort. Also, some still have the misperception that bodybuilding necessarily involves the use of anabolic steroids, which are prohibited in Olympic competitions. Proponents argue that the posing routine requires skill and preparation, and bodybuilding should therefore be considered a sport. In 2003, Joe Weider sold Weider Publications to AMI, which owns The National Enquirer. Ben Weider is still the president of the IFBB. In 2004, contest promoter Wayne DeMilia broke ranks with the IFBB and AMI took over the promotion of the Mr. Olympia contest. # Areas of Bodybuilding Professional bodybuilding In the modern bodybuilding industry "Professional" generally means a bodybuilder who has won qualifying completions as an amateur and has earned a 'pro card' from the IFBB. Professionals earn the right to compete in sanctioned competitions including the Arnold Classic and the Night of Champions. Placings at such competitions in turn earn them the right to compete at the Mr. Olympia; the title is considered to be the highest accolade in the professional bodybuilding field. Natural bodybuilding In natural contests bodybuilders are routinely tested for illegal substances and are banned for any violations from future contests. Testing can be done on urine samples, but in many cases a less expensive polygraph (lie detector) test is performed instead. What qualifies as an "illegal" substance, in the sense that it is prohibited by regulatory bodies, varies between natural federations, and does not necessarily include only substances that are illegal under the laws of the relevant jurisdiction. Anabolic steroids, Prohormone and Diuretics are generally banned in natural organizations. Natural bodybuilding organizations include NANBF (North American Natural Bodybuilding Federation), and the NPA (Natural physique association). Natural bodybuilders assert that their method is more focused on competition and a healthy lifestyle than other forms of bodybuilding. Teenage bodybuilding Bodybuilding also has many competition categories for young entrants. Many current professional bodybuilders started weight training during their teenage years. Bodybuilders such as Arnold Schwarzenegger, Lee Priest and Jay Cutler all started competing when they were teenagers. Today many teenagers compete in bodybuilding competitions. Female bodybuilding In the 1970s, women began to take part in bodybuilding competitions, and was extremely popular for a time. More than ever women are training with weights for exercise purposes with desire for a more attractive body and to prevent bone loss. Many women however still fear that weight training will make them "bulky" and believe weight training is only for men. However strength training has many benefits for women including increased bone mass and prevention of bone loss as well as increased muscle strength and balance. In recent years, the related areas of fitness and figure competition have gained in popularity, providing an alternative for women who choose not to develop the level of muscularity necessary for bodybuilding. The first Ms. Olympia contest in 1980, won by Rachel McLish, would resemble closely what is thought of today as a fitness and figure competition. # Competition For biographies of professional bodybuilders see list of female bodybuilders, list of male professional bodybuilders, and Category:Professional bodybuilders In competitive bodybuilding, bodybuilders aspire to develop and maintain an aesthetically pleasing (by bodybuilding standards) body and balanced physique. The competitors show off their bodies by performing a number of poses - bodybuilders spend time practicing their posing as this has a large effect on how they are judged. A bodybuilder's size and shape are far more important than how much he or she can lift. The sport should therefore not be confused with strongman competition or powerlifting, where the main point is on actual physical strength, or with Olympic weightlifting, where the main point is equally split between strength and technique. Though superficially similar to the casual observer, the fields entail a different regimen of training, diet, and basic motivation. ## Contest preparation The general strategy adopted by most present-day competitive bodybuilders is to make muscle gains for most of the year (known as the "off-season") and approximately 3-4 months from competition attempt to lose body fat (referred to as "cutting"). In doing this some muscle will be lost but the aim is to keep this to a minimum. There are many approaches used but most involve reducing calorie intake and increasing cardio, while monitoring body fat percentage. In the week leading up to a contest, bodybuilders will begin increasing their water intake so as to deregulate the systems in the body associated with water flushing. They will also increase their sodium intake. At the same time they will decrease their carbohydrate consumption in an attempt to "carb deplete". The goal during this week is to deplete the muscles of glycogen. Two days before the show, sodium intake is reduced by half, and then eliminated completely. The day before the show, water is removed from the diet, and diuretics may be introduced. At the same time carbohydrates are re-introduced into the diet to expand the muscles. This is typically known as "carb-loading." The end result is an ultra-lean bodybuilder with full hard muscles and a dry, vascular appearance. Prior to performing on stage, bodybuilders will apply various products to their skin to improve their muscle definition - these include fake tan commonly called "pro tan" (to make the skin darker) and various oils (to make the skin shiny). They will also use weights to "pump up" by forcing blood to their muscles to improve size and vascularity. # Strategy Bodybuilders use three main strategies to maximize muscle hypertrophy: - Strength training through weights or elastic/hydraulic resistance - Specialised nutrition, incorporating extra protein and supplements where necessary - Adequate rest, including sleep and recuperation between workouts ## Weight training Weight training causes micro-tears to the muscles being trained; this is generally known as microtrauma. These micro-tears in the muscle contribute to the soreness felt after exercise, called delayed onset muscle soreness (DOMS). It is the repair to these micro-trauma that result in muscle growth. Normally, this soreness becomes most apparent a day or two after a workout. ## Nutrition The high levels of muscle growth and repair achieved by bodybuilders require a specialized diet. Generally speaking, bodybuilders require more calories than the average person of the same height to support the protein and energy requirements needed to support their training and increase muscle mass. A sub-maintenance level of food energy is combined with cardiovascular exercise to lose body fat in preparation for a contest. The ratios of food energy from carbohydrates, proteins, and fats vary depending on the goals of the bodybuilder. Carbohydrates play an important role for bodybuilders. Carbohydrates give the body energy to deal with the rigors of training and recovery. Bodybuilders seek out low-glycemic polysaccharides and other slowly-digesting carbohydrates, which release energy in a more stable fashion than high-glycemic sugars and starches. This is important as high-glycemic carbohydrates cause a sharp insulin response, which places the body in a state where it is likely to store additional food energy as fat rather than muscle, and which can waste energy that should be directed towards muscle growth. However, bodybuilders frequently do ingest some quickly-digesting sugars (often in form of pure dextrose or maltodextrin) after a workout. This may help to replenish glycogen stores within the muscle, and to stimulate muscle protein synthesis. Protein is probably one of the most important parts of the diet for the bodybuilder to consider. Functional proteins such as motor proteins which include myosin, kinesin, and dynein generate the forces exerted by contracting muscles. Current advice says that bodybuilders should consume 25-30% of protein per total calorie intake to further their goal of maintaining and improving their body composition. This is a widely debated topic, with many arguing that 1 gram of protein per pound of body weight is ideal, some suggesting that less is sufficient, and others recommending 1.5, 2, or more. It is believed that protein needs to be consumed frequently throughout the day, especially during/after a workout, and before sleep. There is also some debate concerning the best type of protein to take. Chicken, beef, pork, fish, eggs and dairy foods are high in protein, as are some nuts, seeds, beans and lentils. Casein or whey are often used to supplement the diet with additional protein. Whey protein is the type of protein contained in many popular brands of protein supplements, and is preferred by many bodybuilders because of its high Biological Value (BV) and quick absorption rates. Bodybuilders usually require higher quality protein with a high BV rather than relying on protein such as soy, which is often avoided due to its estrogenic properties. Still, some nutrition experts believe that soy, flax seeds and many other plants that contain the weak estrogen-like compounds or phytoestrogens can be used beneficially as phytoestrogens compete with this hormone for receptor sites in the male body and can block its actions. This can also include some inhibition of pituitary functions while stimulating the P450 system (the system that eliminates chemicals, hormones, drugs and metabolic waste product from the body) in the liver to more actively process and excrete excess estrogen. Bodybuilders usually split their food intake for the day into 5 to 7 meals of roughly equal nutritional content and attempt to eat at regular intervals (normally between 2 and 3 hours). This method purports to serve two purposes: to limit overindulging as well as increasing basal metabolic rate when compared to the traditional 3 meals a day. However, this has been debunked as the most reliable reasearch using whole-body calorimetry and doubly-labelled water finds no metabolic advantage to eating more frequently. ### Dietary supplements The important role of nutrition in building muscle and losing fat means bodybuilders may consume a wide variety of dietary supplements. Various products are used in an attempt to augment muscle size, increase the rate of fat loss, improve joint health and prevent potential nutrient deficiencies. Scientific consensus supports the effectiveness of only a small number of commercially available supplements when used by healthy, physically active adults. Creatine is probably the most widely used performance enhancing legal supplement. Creatine works by turning into creatine phosphate, which provides an extra phosphorus molecule in the regeneration of ATP. This will provide the body with more energy that lasts longer during short, intense bits of work like weight training. ## Performance enhancing substances Some bodybuilders use drugs to gain an advantage in hypertrophy, especially in professional competitions. Although these substances are illegal without prescription in many countries, in professional bodybuilding anabolic steroids and precursor substances such as prohormones are used very frequently. Anabolic steroids cause muscle hypertrophy of both types (I and II) of muscle fibers caused likely by an increased synthesis of muscle proteins. Some negative side-effects accompany steroid abuse, such as hepatotoxicity, gynecomastia, acne, male pattern baldness and a temporary decline in the body's own testosterone production, which can cause testicular atrophy. Growth Hormone (GH) and insulin are also used. GH is relatively expensive compared to steroids, while insulin is very readily available yet fatal if misused. See Growth hormone treatment for bodybuilding. ## Rest Although muscle stimulation occurs in the gym lifting weights, muscle growth occurs afterward during rest. Without adequate rest and sleep, muscles do not have an opportunity to recover and build. About eight hours of sleep a night is desirable for the bodybuilder to be refreshed, although this varies from person to person. Additionally, many athletes find a daytime nap further increases their body's ability to build muscle. Some bodybuilders take several naps per day, during peak anabolic phases. ## Overtraining Overtraining refers to when a bodybuilder has trained to the point where his workload exceeds his recovery capacity. There are many reasons that overtraining occurs, including lack of adequate nutrition, lack of recovery time between workouts, insufficient sleep, and training at a high intensity for too long (a lack of splitting apart workouts). Training at a high intensity too frequently also stimulates the central nervous system (CNS) and can result in a hyper-adrenergic state that interferes with sleep patterns. To avoid overtraining, intense frequent training must be met with at least an equal amount of purposeful recovery. Timely provision of carbohydrates, proteins, and various micronutrients such as vitamins, minerals, phytochemicals, even nutritional supplements are acutely critical. It has been argued that overtraining can be beneficial. One article published by Muscle & Fitness magazine stated that you can "Overtrain for Big Gains". It suggested that if one is planning a restful holiday and they do not wish to inhibit their bodybuilding lifestyle too much, they should overtrain before taking the holiday, so the body can rest easily and recuperate and grow. Overtraining can be used advantageously, as when a bodybuilder is purposely overtrained for a brief period of time to super compensate during a regeneration phase. These are known as "shock micro-cycles" and were a key training technique used by Soviet athletes. However, the vast majority of overtraining that occurs in average bodybuilders is generally unplanned and completely unnecessary.	Bodybuilder Bodybuilding is the process of maximizing muscle hypertrophy through the combination of weight training, sufficient caloric intake, and rest. Someone who engages in this activity is referred to as a bodybuilder. As a sport, called competitive bodybuilding, bodybuilders display their physiques to a panel of judges, who assign points based on their aesthetic appearance. The muscles are revealed through a combination of fat loss, oils, and tanning (or tanning lotions) which combined with lighting make the definition of the muscle group more distinct. Famous bodybuilders include Arnold Schwarzenegger, Dorian Yates, Lou Ferrigno, Franco Columbu, Frank Zane, Lee Haney, Ronnie Coleman, and Jay Cutler. # History ## Early years The "Early Years" of Bodybuilding are considered to be the period between 1880 and 1930. Bodybuilding (the art of displaying the muscles) did not really exist prior to the late 19th century, when it was promoted by a man from Prussia named Eugen Sandow,[1] who is now generally referred to as "The Father of Modern Bodybuilding". He is credited as being a pioneer of the sport because he allowed an audience to enjoy viewing his physique in "muscle display performances". Although audiences were thrilled to see a well-developed physique, those men simply displayed their bodies as part of strength demonstrations or wrestling matches. Sandow had a stage show built around these displays through his manager, Florenz Ziegfeld. He became so successful at it, he later created several businesses around his fame and was among the first to market products branded with his name alone. As he became more popular, he was credited with inventing and selling the first exercise equipment for the masses (machined dumbbells, spring pulleys and tension bands). Sandow was a strong advocate of "the Grecian Ideal" (this was a standard where a mathematical "ideal" was set up and the "perfect physique" was close to the proportions of ancient Greek and Roman statues from classical times). This is how Sandow built his own physique and in the early years, men were judged by how closely they matched these "ideal" proportions. Sandow organised the first bodybuilding contest on 14 September, 1901 called the "Great Competition" and held in the Royal Albert Hall, London, UK. Judged by himself, Sir Charles Lawes, and Sir Arthur Conan Doyle, the contest was a huge success and was sold out and hundreds of physical culture enthusiasts were turned away. The trophy presented to the winner was a bronze statue of Sandow himself sculpted by Frederick Pomeroy. The winner was William L. Murray of Nottingham, England. The most prestigious bodybuilding contest today is the Mr. Olympia, and since 1977, the winner has been presented with the same bronze statue of Sandow that he himself presented to the winner at the first contest.[2] On 16 January, 1904, the first large-scale bodybuilding competition in America took place at Madison Square Garden in New York City. The winner was Al Treloar and he was declared "The Most Perfectly Developed Man in the World". Treloar won a $1,000 cash prize, a substantial sum at that time. Two weeks later, Thomas Edison made a film of Al Treloar's posing routine. Edison also made two films of Sandow a few years before, making him the man who made the first three motion pictures featuring a bodybuilder. In the early 20th century, Bernarr Macfadden and Charles Atlas, continued to promote bodybuilding across the world. Alois P. Swoboda was an early pioneer in America and the man whom Charles Atlas credited with his success in his statement: "Everything that I know I learned from A. P. (Alois) Swoboda."[citation needed] Other important bodybuilders in the early history of bodybuilding prior to 1930 include: Earle Liederman (writer of some of the earliest bodybuilding instruction books), Seigmund Breitbart (famous Jewish bodybuilder), Georg Hackenschmidt, George F. Jowett, Maxick (a pioneer in the art of posing), Monte Saldo, Launceston Elliot, Sig Klein, Sgt. Alfred Moss, Joe Nordquist, Lionel Strongfort (Strongfortism), Gustav Fristensky (the Czech champion), and Alan C. Mead, who became an impressive muscle champion despite the fact that he lost a leg in World War I. ## The "Golden Age" The period of around 1940 to 1970 is often referred to as the "Golden Age" of bodybuilding because of changes in the aesthetic for more mass, as well as muscular symmetry and definition, which characterised the "early years". This was due in large part to the advent of World War II, which inspired many young men to be bigger, stronger and more aggressive in their attitudes. This was accomplished by improved training techniques, better nutrition and more effective equipment. Several important publications came into being, as well, and new contests emerged as the popularity of the sport grew. This period of bodybuilding was typified at Muscle Beach in Venice, California. Famous names in bodybuilding from this period included Steve Reeves (notable in his day for portraying Hercules and other sword-and-sandal heroes),Clancy Ross, Reg Park, John Grimek, Larry Scott, Bill Pearl, and Irvin "Zabo" Koszewski. The rise in popularity of the Amateur Athletic Union (AAU) added a bodybuilding competition to their existing weightlifting contest in 1939 - and the following year this competition was named AAU Mr. America. Around the mid-1940s most bodybuilders became disgruntled with the AAU since they only allowed amateur competitors and they placed more focus on the Olympic sport of weightlifting. This caused brothers Ben and Joe Weider to form the International Federation of BodyBuilders (IFBB) - which organized their competition IFBB Mr. America, which was open to professional athletes. In 1950, another organization, the National Amateur Bodybuilders Association (NABBA) started their NABBA Mr. Universe contest in the UK. Another major contest, Mr. Olympia was first held in 1965 - and this is currently the most prestigious title in bodybuilding. Initially contests were only for men, but the NABBA added Miss Universe in 1965 and Ms. Olympia was started in 1980. (For more, see female bodybuilding.) ## 1970s onwards In the 1970s, bodybuilding had major publicity thanks to Arnold Schwarzenegger and the 1977 film Pumping Iron. By this time the IFBB dominated the sport and the AAU took a back seat. The National Physique Committee (NPC) was formed in 1981 by Jim Manion, who had just stepped down as chairman of the AAU Physique Committee. The NPC has gone on to become the most successful bodybuilding organization in the U.S., and is the amateur division of the IFBB. The late 1980s and early 1990s saw the decline of AAU sponsored bodybuilding contests. In 1999, the AAU voted to discontinue its bodybuilding events. This period also saw the rise of anabolic steroids used both in bodybuilding and many other sports. To combat this, and to be allowed to be an IOC member, the IFBB introduced doping tests for both steroids and other banned substances. Although doping tests occurred, the majority of professional bodybuilders still used anabolic steroids for competition. During the 1970s the use of anabolic steroids was openly discussed partly due to the fact they were legal.[3] However the U.S. Congress in the Anabolic Steroid Control Act of 1990 placed anabolic steroids into Schedule III of the Controlled substance act (CSA). In 1990, wrestling promoter Vince McMahon announced he was forming a new bodybuilding organization, the World Bodybuilding Federation (WBF). McMahon wanted to bring WWF-style showmanship and bigger prize money to the sport of bodybuilding. McMahon signed 13 competitors to lucrative long-term contracts, something virtually unheard of in bodybuilding up until then. Most of the WBF competitors immediately abandoned the IFBB. In response to the WBF's formation, IFBB president Ben Weider blacklisted all the bodybuilders who had signed with the WBF. The IFBB also quietly stopped testing their athletes for anabolic steroid use since it was difficult to compete thus with a new organization which did not test for steroids. In 1992, Vince McMahon instituted drug testing for WBF athletes because he and the WWF were under investigation by the federal government for alleged involvement in anabolic steroid trafficking. The result was that the competitors in the 1992 WBF contest looked sub-par, according to some contemporary accounts. McMahon formally dissolved the WBF in July, 1992. Reasons for this probably included lack of income from the pay-per-view broadcasts of the WBF contests, slow sales of the WBF's magazine Bodybuilding Lifestyles (which later became WBF Magazine), and the expense of paying multiple 6-figure contracts as well as producing two TV shows and a monthly magazine. However, the formation of the WBF had two positive effects for the IFBB athletes: (1) it caused IFBB founder Joe Weider to sign many of his top stars to contracts, and (2) it caused the IFBB to raise prize money in its sanctioned contests. Joe Weider eventually offered to accept the WBF bodybuilders back into the IFBB for a fine of 10% of their former yearly WBF salary. In the early 2000s, the IFBB was attempting to make bodybuilding an Olympic sport. It obtained full IOC membership in 2000 and was attempting to get approved as a demonstration event at the Olympics which would hopefully lead to it being added as a full contest. This did not happen. Olympic recognition for bodybuilding remains controversial since some argue that bodybuilding is not a sport because the actual contest does not involve athletic effort. Also, some still have the misperception that bodybuilding necessarily involves the use of anabolic steroids, which are prohibited in Olympic competitions. Proponents argue that the posing routine requires skill and preparation, and bodybuilding should therefore be considered a sport. In 2003, Joe Weider sold Weider Publications to AMI, which owns The National Enquirer. Ben Weider is still the president of the IFBB. In 2004, contest promoter Wayne DeMilia broke ranks with the IFBB and AMI took over the promotion of the Mr. Olympia contest. # Areas of Bodybuilding Professional bodybuilding In the modern bodybuilding industry "Professional" generally means a bodybuilder who has won qualifying completions as an amateur and has earned a 'pro card' from the IFBB. Professionals earn the right to compete in sanctioned competitions including the Arnold Classic and the Night of Champions. Placings at such competitions in turn earn them the right to compete at the Mr. Olympia; the title is considered to be the highest accolade in the professional bodybuilding field. Natural bodybuilding In natural contests bodybuilders are routinely tested for illegal substances and are banned for any violations from future contests. Testing can be done on urine samples, but in many cases a less expensive polygraph (lie detector) test is performed instead. What qualifies as an "illegal" substance, in the sense that it is prohibited by regulatory bodies, varies between natural federations, and does not necessarily include only substances that are illegal under the laws of the relevant jurisdiction. Anabolic steroids, Prohormone and Diuretics are generally banned in natural organizations. Natural bodybuilding organizations include NANBF (North American Natural Bodybuilding Federation), and the NPA (Natural physique association). Natural bodybuilders assert that their method is more focused on competition and a healthy lifestyle than other forms of bodybuilding. Teenage bodybuilding Bodybuilding also has many competition categories for young entrants. Many current professional bodybuilders started weight training during their teenage years. Bodybuilders such as Arnold Schwarzenegger, Lee Priest and Jay Cutler all started competing when they were teenagers. Today many teenagers compete in bodybuilding competitions. Female bodybuilding In the 1970s, women began to take part in bodybuilding competitions, and was extremely popular for a time. More than ever women are training with weights for exercise purposes with desire for a more attractive body and to prevent bone loss.[4] Many women however still fear that weight training will make them "bulky" and believe weight training is only for men. However strength training has many benefits for women including increased bone mass and prevention of bone loss as well as increased muscle strength and balance.[5][6] In recent years, the related areas of fitness and figure competition have gained in popularity, providing an alternative for women who choose not to develop the level of muscularity necessary for bodybuilding. The first Ms. Olympia contest in 1980, won by Rachel McLish, would resemble closely what is thought of today as a fitness and figure competition. # Competition For biographies of professional bodybuilders see list of female bodybuilders, list of male professional bodybuilders, and Category:Professional bodybuilders In competitive bodybuilding, bodybuilders aspire to develop and maintain an aesthetically pleasing (by bodybuilding standards) body and balanced physique. The competitors show off their bodies by performing a number of poses - bodybuilders spend time practicing their posing as this has a large effect on how they are judged. A bodybuilder's size and shape are far more important than how much he or she can lift. The sport should therefore not be confused with strongman competition or powerlifting, where the main point is on actual physical strength, or with Olympic weightlifting, where the main point is equally split between strength and technique. Though superficially similar to the casual observer, the fields entail a different regimen of training, diet, and basic motivation. ## Contest preparation The general strategy adopted by most present-day competitive bodybuilders is to make muscle gains for most of the year (known as the "off-season") and approximately 3-4 months from competition attempt to lose body fat (referred to as "cutting"). In doing this some muscle will be lost but the aim is to keep this to a minimum. There are many approaches used but most involve reducing calorie intake and increasing cardio, while monitoring body fat percentage. In the week leading up to a contest, bodybuilders will begin increasing their water intake so as to deregulate the systems in the body associated with water flushing. They will also increase their sodium intake. At the same time they will decrease their carbohydrate consumption in an attempt to "carb deplete". The goal during this week is to deplete the muscles of glycogen. Two days before the show, sodium intake is reduced by half, and then eliminated completely. The day before the show, water is removed from the diet, and diuretics may be introduced. At the same time carbohydrates are re-introduced into the diet to expand the muscles. This is typically known as "carb-loading." The end result is an ultra-lean bodybuilder with full hard muscles and a dry, vascular appearance. Prior to performing on stage, bodybuilders will apply various products to their skin to improve their muscle definition - these include fake tan commonly called "pro tan" (to make the skin darker) and various oils (to make the skin shiny). They will also use weights to "pump up" by forcing blood to their muscles to improve size and vascularity. # Strategy Bodybuilders use three main strategies to maximize muscle hypertrophy: - Strength training through weights or elastic/hydraulic resistance - Specialised nutrition, incorporating extra protein and supplements where necessary - Adequate rest, including sleep and recuperation between workouts ## Weight training Weight training causes micro-tears to the muscles being trained; this is generally known as microtrauma. These micro-tears in the muscle contribute to the soreness felt after exercise, called delayed onset muscle soreness (DOMS). It is the repair to these micro-trauma that result in muscle growth. Normally, this soreness becomes most apparent a day or two after a workout.[7] ## Nutrition The high levels of muscle growth and repair achieved by bodybuilders require a specialized diet. Generally speaking, bodybuilders require more calories than the average person of the same height to support the protein and energy requirements needed to support their training and increase muscle mass. A sub-maintenance level of food energy is combined with cardiovascular exercise to lose body fat in preparation for a contest. The ratios of food energy from carbohydrates, proteins, and fats vary depending on the goals of the bodybuilder.[8] Carbohydrates play an important role for bodybuilders. Carbohydrates give the body energy to deal with the rigors of training and recovery. Bodybuilders seek out low-glycemic polysaccharides and other slowly-digesting carbohydrates, which release energy in a more stable fashion than high-glycemic sugars and starches. This is important as high-glycemic carbohydrates cause a sharp insulin response, which places the body in a state where it is likely to store additional food energy as fat rather than muscle, and which can waste energy that should be directed towards muscle growth. However, bodybuilders frequently do ingest some quickly-digesting sugars (often in form of pure dextrose or maltodextrin) after a workout. This may help to replenish glycogen stores within the muscle, and to stimulate muscle protein synthesis.[9] Protein is probably one of the most important parts of the diet for the bodybuilder to consider. Functional proteins such as motor proteins which include myosin, kinesin, and dynein generate the forces exerted by contracting muscles. Current advice says that bodybuilders should consume 25-30% of protein per total calorie intake to further their goal of maintaining and improving their body composition.[10] This is a widely debated topic, with many arguing that 1 gram of protein per pound of body weight is ideal, some suggesting that less is sufficient, and others recommending 1.5, 2, or more.[11][12][13][14] It is believed that protein needs to be consumed frequently throughout the day, especially during/after a workout, and before sleep.[15] There is also some debate concerning the best type of protein to take. Chicken, beef, pork, fish, eggs and dairy foods are high in protein, as are some nuts, seeds, beans and lentils. Casein or whey are often used to supplement the diet with additional protein. Whey protein is the type of protein contained in many popular brands of protein supplements, and is preferred by many bodybuilders because of its high Biological Value (BV) and quick absorption rates. Bodybuilders usually require higher quality protein with a high BV rather than relying on protein such as soy, which is often avoided due to its estrogenic properties.[16] Still, some nutrition experts believe that soy, flax seeds and many other plants that contain the weak estrogen-like compounds or phytoestrogens can be used beneficially as phytoestrogens compete with this hormone for receptor sites in the male body and can block its actions. This can also include some inhibition of pituitary functions while stimulating the P450 system (the system that eliminates chemicals, hormones, drugs and metabolic waste product from the body) in the liver to more actively process and excrete excess estrogen.[17][18] Bodybuilders usually split their food intake for the day into 5 to 7 meals of roughly equal nutritional content and attempt to eat at regular intervals (normally between 2 and 3 hours). This method purports to serve two purposes: to limit overindulging as well as increasing basal metabolic rate when compared to the traditional 3 meals a day. However, this has been debunked as the most reliable reasearch using whole-body calorimetry and doubly-labelled water finds no metabolic advantage to eating more frequently.[19][20] ### Dietary supplements The important role of nutrition in building muscle and losing fat means bodybuilders may consume a wide variety of dietary supplements.[21] Various products are used in an attempt to augment muscle size, increase the rate of fat loss, improve joint health and prevent potential nutrient deficiencies. Scientific consensus supports the effectiveness of only a small number of commercially available supplements when used by healthy, physically active adults[citation needed]. Creatine is probably the most widely used performance enhancing legal supplement. Creatine works by turning into creatine phosphate, which provides an extra phosphorus molecule in the regeneration of ATP. This will provide the body with more energy that lasts longer during short, intense bits of work like weight training. ## Performance enhancing substances Some bodybuilders use drugs to gain an advantage in hypertrophy, especially in professional competitions. Although these substances are illegal without prescription in many countries, in professional bodybuilding anabolic steroids and precursor substances such as prohormones are used very frequently. Anabolic steroids cause muscle hypertrophy of both types (I and II) of muscle fibers caused likely by an increased synthesis of muscle proteins. Some negative side-effects accompany steroid abuse, such as hepatotoxicity, gynecomastia, acne, male pattern baldness and a temporary decline in the body's own testosterone production, which can cause testicular atrophy.[22][23][24] Growth Hormone (GH) and insulin are also used. GH is relatively expensive compared to steroids, while insulin is very readily available yet fatal if misused. See Growth hormone treatment for bodybuilding. ## Rest Although muscle stimulation occurs in the gym lifting weights, muscle growth occurs afterward during rest. Without adequate rest and sleep, muscles do not have an opportunity to recover and build. About eight hours of sleep a night is desirable for the bodybuilder to be refreshed, although this varies from person to person. Additionally, many athletes find a daytime nap further increases their body's ability to build muscle. Some bodybuilders take several naps per day, during peak anabolic phases. ## Overtraining Overtraining refers to when a bodybuilder has trained to the point where his workload exceeds his recovery capacity. There are many reasons that overtraining occurs, including lack of adequate nutrition, lack of recovery time between workouts, insufficient sleep, and training at a high intensity for too long (a lack of splitting apart workouts). Training at a high intensity too frequently also stimulates the central nervous system (CNS) and can result in a hyper-adrenergic state that interferes with sleep patterns.[25] To avoid overtraining, intense frequent training must be met with at least an equal amount of purposeful recovery. Timely provision of carbohydrates, proteins, and various micronutrients such as vitamins, minerals, phytochemicals, even nutritional supplements are acutely critical. It has been argued that overtraining can be beneficial. One article published by Muscle & Fitness magazine stated that you can "Overtrain for Big Gains". It suggested that if one is planning a restful holiday and they do not wish to inhibit their bodybuilding lifestyle too much, they should overtrain before taking the holiday, so the body can rest easily and recuperate and grow. Overtraining can be used advantageously, as when a bodybuilder is purposely overtrained for a brief period of time to super compensate during a regeneration phase. These are known as "shock micro-cycles" and were a key training technique used by Soviet athletes.[26] However, the vast majority of overtraining that occurs in average bodybuilders is generally unplanned and completely unnecessary.[27]	https://www.wikidoc.org/index.php/Bodybuilder
b19b45bb2424c395f75d0e63557bd0858bc19651	wikidoc	Bohr effect	Bohr effect The Bohr effect is a property of hemoglobin first described by the Danish physiologist Christian Bohr in 1904, and often erroneously attributed to his son, physicist Niels Bohr, which states that in the presence of carbon dioxide, the oxygen affinity for dissociation of respiratory pigments, such as hemoglobin decreases; because of the Bohr effect, an increase in blood carbon dioxide level or a decrease in pH causes hemoglobin to bind to oxygen with less affinity. This effect facilitates oxygen transport as hemoglobin binds to oxygen in the lungs, but then releases it in the tissues, particularly those tissues in most need of oxygen. When a tissue's metabolic rate increases, its carbon dioxide production increases. The carbon dioxide is quickly converted into bicarbonate molecules and acidic protons by the enzyme carbonic anhydrase: This causes the pH of the tissue to decrease, and so increases the dissociation of oxygen from hemoglobin, allowing the tissue to obtain enough oxygen to meet its demands. The dissociation curve shifts to the right when carbon dioxide or hydrogen ion concentration is increased. This facilitates increased oxygen dumping. This makes sense because increased CO2 concentration and lactic acid build-up occur when the muscles need more oxygen. Changing hemoglobin's oxygen affinity is the body's way of adapting quickly to this problem. In the Hiroshima variant hemoglobinopathy the Bohr effect is diminished so the hemoglobin has a higher affinity for oxygen and tissue may suffer minor oxygen starvation during high work.	Bohr effect Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The Bohr effect is a property of hemoglobin first described by the Danish physiologist Christian Bohr in 1904, and often erroneously attributed to his son, physicist Niels Bohr, which states that in the presence of carbon dioxide, the oxygen affinity for dissociation of respiratory pigments, such as hemoglobin decreases; because of the Bohr effect, an increase in blood carbon dioxide level or a decrease in pH causes hemoglobin to bind to oxygen with less affinity. This effect facilitates oxygen transport as hemoglobin binds to oxygen in the lungs, but then releases it in the tissues, particularly those tissues in most need of oxygen. When a tissue's metabolic rate increases, its carbon dioxide production increases. The carbon dioxide is quickly converted into bicarbonate molecules and acidic protons by the enzyme carbonic anhydrase: This causes the pH of the tissue to decrease, and so increases the dissociation of oxygen from hemoglobin, allowing the tissue to obtain enough oxygen to meet its demands. The dissociation curve shifts to the right when carbon dioxide or hydrogen ion concentration is increased. This facilitates increased oxygen dumping. This makes sense because increased CO2 concentration and lactic acid build-up occur when the muscles need more oxygen. Changing hemoglobin's oxygen affinity is the body's way of adapting quickly to this problem. In the Hiroshima variant hemoglobinopathy the Bohr effect is diminished so the hemoglobin has a higher affinity for oxygen and tissue may suffer minor oxygen starvation during high work.	https://www.wikidoc.org/index.php/Bohr_Effect
879e964b274fcf6a53c86822074dc120f2d2dbd4	wikidoc	Bond energy	Bond energy In chemistry, bond energy (E) is a measure of bond strength in a chemical bond. For example the carbon-hydrogen bond energy in methane E(C–H) is the enthalpy change involved with breaking up one molecule of methane into a carbon atom and 4 hydrogen radicals divided by 4. Bond energy (E) should not be confused with bond dissociation energy. Another example: an O–H bond of a water molecule (H–O–H) has 493.4 kJ mol-1 of bond dissociation energy, and 424.4 kJ mol-1 is needed to cleave the remaining O–H bond. The bond energy of the O–H bonds in water is 458.9 kJ mol-1, which is the average of the values. Some bond energy trends (units are in kcal/mol and (kJ/mol)) : # Bond energy/distance correlation Bond strength (energy) can be directly related to the bond distance. Therefore we can use the metallic, ionic, or covalent radii of each atom in the molecule to determine the bond strength. For example, the covalent radius of boron is estimated at 83.0 pm, but the bond length of B–B in B2Cl4 is 175 pm, a significantly larger value. This would indicate that the bond between the two boron atoms is a rather weak single bond. In another example, the metallic radius of rhenium is 137.5 pm, with a Re–Re bond length of 224 pm in the compound Re2Cl8. From this data, we can conclude that the bond is a very strong bond or a quadruple bond. This method of determination is most useful for covalently bonded compounds . # What determines Bonding Energy There are several contributing factors but usually the most important is the difference in the electronegativity of the two atoms bonding together.	Bond energy In chemistry, bond energy (E) is a measure of bond strength in a chemical bond. For example the carbon-hydrogen bond energy in methane E(C–H) is the enthalpy change involved with breaking up one molecule of methane into a carbon atom and 4 hydrogen radicals divided by 4. Bond energy (E) should not be confused with bond dissociation energy. Another example: an O–H bond of a water molecule (H–O–H) has 493.4 kJ mol-1 of bond dissociation energy, and 424.4 kJ mol-1 is needed to cleave the remaining O–H bond. The bond energy of the O–H bonds in water is 458.9 kJ mol-1, which is the average of the values. Some bond energy trends (units are in kcal/mol and (kJ/mol)) [1]: # Bond energy/distance correlation Bond strength (energy) can be directly related to the bond distance. Therefore we can use the metallic, ionic, or covalent radii of each atom in the molecule to determine the bond strength. For example, the covalent radius of boron is estimated at 83.0 pm, but the bond length of B–B in B2Cl4 is 175 pm, a significantly larger value. This would indicate that the bond between the two boron atoms is a rather weak single bond. In another example, the metallic radius of rhenium is 137.5 pm, with a Re–Re bond length of 224 pm in the compound Re2Cl8. From this data, we can conclude that the bond is a very strong bond or a quadruple bond. This method of determination is most useful for covalently bonded compounds [2]. # What determines Bonding Energy There are several contributing factors but usually the most important is the difference in the electronegativity of the two atoms bonding together. [3]	https://www.wikidoc.org/index.php/Bond_energy
a4e153326594577b2fff24eb88be339387200031	wikidoc	Bone marrow	Bone marrow # Overview Bone marrow (or medulla ossea) is the soft tissue found in the hollow interior of bones. In adults, marrow in large bones produces new blood cells. It constitutes 4% of total body weight, i.e. approximately 2.6 kg (5.7 lbs.) in adults. # Anatomy ## Marrow types There are two types of bone marrow: red marrow (consisting mainly of myeloid tissue) and yellow marrow (consisting mainly of fat cells). Red blood cells, platelets and most white blood cells arise in red marrow; some white blood cells develop in yellow marrow. Both types of bone marrow contain numerous blood vessels and capillaries. At birth, all bone marrow is red. With age, more and more of it is converted to the yellow type. About half of the bone marrow is red. Red marrow is found mainly in the flat bones, such as the hip bone, breast bone, skull, ribs, vertebrae and shoulder blades, and in the cancellous ("spongy") material at the proximal ends of the long bones femur and humerus. Yellow marrow is found in the hollow interior of the middle portion of long bones. In cases of severe blood loss, the body can convert yellow marrow back to red marrow in order to increase blood cell production. ## Stroma The stroma of the bone marrow is all tissue that isn't directly involved in the primary function of hematopoiesis. The yellow bone marrow belongs here, and makes the majority of the bone marrow stroma, in addition to stromal cells located in the red bone marrow. Still, the stroma is indirectly involved in hematopoiesis, since it provides the hematopoietic microenvironment that facilitates hematopoiesis by the parenchymal cells. For instance, they generate colony stimulating factors, affecting hematopoiesis. Cells that constitute the bone marrow stroma are: - fibroblasts (reticular connective tissue) - macrophages - adipocytes - osteoblasts - blood vessels (sinusoid) Macrophages contribute especially to red blood cell production. They deliver iron for hemoglobin-production. ### Bone marrow barrier The blood vessels constitute a barrier, inhibiting immature blood cells from leaving the bone marrow. Only mature blood cells contain the membrane proteins required to attach to and pass the blood vessel endothelium. Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood. ### Stem cells The bone marrow stroma contain mesenchymal stem cells (also called marrow stromal cells). These cells are multipotent stem cells that can differentiate into a variety of cell types. Cell types that MSCs have been shown to differentiate into in vitro or in vivo include osteoblasts, chondrocytes, myocytes, adipocytes, and, as described lately, beta-pancreatic islets cells. They can also transdifferentiate into neuronal cells. ## Compartmentalization There is biologic compartmentalization in the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance, erythrocytes, macrophages and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow. # Types of stem cells Bone marrow contains three types of stem cells: - Hematopoietic stem cells give rise to the three classes of blood cells that are found in the circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets (thrombocytes). - Mesenchymal stem cells are found arrayed around the central sinus in the bone marrow. They have the capability to differentiate into osteoblasts, chondrocytes, myocytes, and many other types of cells. They also function as "gatekeeper" cells of the bone marrow. - Endothelial stem cells # Diseases involving the bone marrow The normal bone marrow architecture can be displaced by malignancies or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets. In addition, cancers of the hematologic progenitor cells in the bone marrow can arise; these are the leukemias. To diagnose diseases involving the bone marrow, a bone marrow aspiration is sometimes performed. This typically involves using a hollow needle to acquire a sample of red bone marrow from the crest of the ilium under general or local anesthesia. The average amount of cells in a leg bone is 4410783 00000. Exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow and will therefore result in a depressed immune system. Many of the symptoms of radiation sickness are due to damage to the bone marrow cells. # Examination Bone marrow examination is the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, anemia, and pancytopenia. The bone marrow produces the cellular elements of the blood, including platelets, red blood cells and white blood cells. While much information can be gleaned by testing the blood itself (drawn from a vein by phlebotomy), it is sometimes necessary to examine the source of the blood cells in the bone marrow to obtain more information on hematopoiesis; this is the role of bone marrow aspiration and biopsy. (Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey, and Kyoto University - Japan, and Hospital Universitario La Fe Servicio Hematologia) - A Wright's stained bone marrow aspirate smear from a patient with leukemia. - Bone marrow aspiration in multiple myeloma - Bone marrow biopsia in aplastic anemia - Bone marrow biopsy in multiple myeloma - Bone marrow in idiopathic myelofibrosis - Bone marrow in megaloblastic anemia - Bone marrow in megaloblastic anemia - Bone marrow in multiple myeloma - Bone marrow in multiple myeloma # Donation and transplantation of bone marrow It is possible to take hematopoietic stem cells from one person and then infuse them into another person (Allogenic) or into the same person at a later time (Autologous). If donor and recipient are compatible, these infused cells will then travel to the bone marrow and initiate blood cell production. Transplantation from one person to another is performed in severe cases of disease of the bone marrow. The patient's marrow is first killed off with drugs or radiation, and then the new stem cells are introduced. Before radiation therapy or chemotherapy in cases of cancer, some of the patient's hematopoietic stem cells are sometimes harvested and later infused back when the therapy is finished to restore the immune system. ## Harvesting The stem cells are harvested directly from the red marrow in the crest of the ilium, usually under general anesthesia. Contrary to popular belief, it is a minimally invasive outpatient procedure with only minor discomfort. Another option is to administer certain drugs that stimulate the release of stem cells from the bone marrow into circulating blood. An IV is inserted into the donor's arm, and the stem cells are filtered out of the blood. The procedure is similar to donating blood or platelets. It may also be taken from the sternum. The tibia may seem a good source, since it is very superficial. However, except in children, this bonemarrow doesn't contain any substantial amount of red bone marrow, but rather only yellow bone marrow. In newborns, stem cells may be retrieved from the umbilical cord. # Bone marrow: Metastatic Adenocarcinoma # Bone marrow as a food Though once used in various preparations, including pemmican, bone marrow for human consumption in America has recently fallen out of favor as a food. Now, it is commonly used only as a flavoring for soups and sauces, although dishes with intact bone marrow can still be found in some European restaurants. Bone marrow is a source of protein and high in monounsaturated fats. These fats are known to decrease LDL cholesterol levels resulting in a reduced risk of cardiovascular disease, prompting some to make bone marrow a dietary staple. The actual health effects of the addition of bone marrow to the diet remain unclear.	Bone marrow Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Bone marrow (or medulla ossea) is the soft tissue found in the hollow interior of bones. In adults, marrow in large bones produces new blood cells. It constitutes 4%[1] of total body weight, i.e. approximately 2.6 kg (5.7 lbs.) in adults. # Anatomy ## Marrow types There are two types of bone marrow: red marrow (consisting mainly of myeloid tissue) and yellow marrow (consisting mainly of fat cells). Red blood cells, platelets and most white blood cells arise in red marrow; some white blood cells develop in yellow marrow. Both types of bone marrow contain numerous blood vessels and capillaries. At birth, all bone marrow is red. With age, more and more of it is converted to the yellow type. About half of the bone marrow is red. [1] Red marrow is found mainly in the flat bones, such as the hip bone, breast bone, skull, ribs, vertebrae and shoulder blades, and in the cancellous ("spongy") material at the proximal ends of the long bones femur and humerus. Yellow marrow is found in the hollow interior of the middle portion of long bones. In cases of severe blood loss, the body can convert yellow marrow back to red marrow in order to increase blood cell production. ## Stroma The stroma of the bone marrow is all tissue that isn't directly involved in the primary function of hematopoiesis. The yellow bone marrow belongs here, and makes the majority of the bone marrow stroma, in addition to stromal cells located in the red bone marrow. Still, the stroma is indirectly involved in hematopoiesis, since it provides the hematopoietic microenvironment that facilitates hematopoiesis by the parenchymal cells. For instance, they generate colony stimulating factors, affecting hematopoiesis. Cells that constitute the bone marrow stroma are: - fibroblasts (reticular connective tissue) - macrophages - adipocytes - osteoblasts - blood vessels (sinusoid) Macrophages contribute especially to red blood cell production. They deliver iron for hemoglobin-production. ### Bone marrow barrier The blood vessels constitute a barrier, inhibiting immature blood cells from leaving the bone marrow. Only mature blood cells contain the membrane proteins required to attach to and pass the blood vessel endothelium. Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood. ### Stem cells The bone marrow stroma contain mesenchymal stem cells (also called marrow stromal cells). These cells are multipotent stem cells that can differentiate into a variety of cell types. Cell types that MSCs have been shown to differentiate into in vitro or in vivo include osteoblasts, chondrocytes, myocytes, adipocytes, and, as described lately, beta-pancreatic islets cells. They can also transdifferentiate into neuronal cells. ## Compartmentalization There is biologic compartmentalization in the bone marrow, in that certain cell types tend to aggregate in specific areas. For instance, erythrocytes, macrophages and their precursors tend to gather around blood vessels, while granulocytes gather at the borders of the bone marrow. # Types of stem cells Bone marrow contains three types of stem cells:[2] - Hematopoietic stem cells give rise to the three classes of blood cells that are found in the circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets (thrombocytes). - Mesenchymal stem cells are found arrayed around the central sinus in the bone marrow. They have the capability to differentiate into osteoblasts, chondrocytes, myocytes, and many other types of cells. They also function as "gatekeeper" cells of the bone marrow. - Endothelial stem cells # Diseases involving the bone marrow Click here to read more about bone marrow disorders. The normal bone marrow architecture can be displaced by malignancies or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets. In addition, cancers of the hematologic progenitor cells in the bone marrow can arise; these are the leukemias. To diagnose diseases involving the bone marrow, a bone marrow aspiration is sometimes performed. This typically involves using a hollow needle to acquire a sample of red bone marrow from the crest of the ilium under general or local anesthesia. The average amount of cells in a leg bone is 4410783 00000. Exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow and will therefore result in a depressed immune system. Many of the symptoms of radiation sickness are due to damage to the bone marrow cells. # Examination Bone marrow examination is the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, anemia, and pancytopenia. The bone marrow produces the cellular elements of the blood, including platelets, red blood cells and white blood cells. While much information can be gleaned by testing the blood itself (drawn from a vein by phlebotomy), it is sometimes necessary to examine the source of the blood cells in the bone marrow to obtain more information on hematopoiesis; this is the role of bone marrow aspiration and biopsy. (Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey, and Kyoto University - Japan, and Hospital Universitario La Fe Servicio Hematologia) - A Wright's stained bone marrow aspirate smear from a patient with leukemia. - Bone marrow aspiration in multiple myeloma - Bone marrow biopsia in aplastic anemia - Bone marrow biopsy in multiple myeloma - Bone marrow in idiopathic myelofibrosis - Bone marrow in megaloblastic anemia - Bone marrow in megaloblastic anemia - Bone marrow in multiple myeloma - Bone marrow in multiple myeloma # Donation and transplantation of bone marrow It is possible to take hematopoietic stem cells from one person and then infuse them into another person (Allogenic) or into the same person at a later time (Autologous). If donor and recipient are compatible, these infused cells will then travel to the bone marrow and initiate blood cell production. Transplantation from one person to another is performed in severe cases of disease of the bone marrow. The patient's marrow is first killed off with drugs or radiation, and then the new stem cells are introduced. Before radiation therapy or chemotherapy in cases of cancer, some of the patient's hematopoietic stem cells are sometimes harvested and later infused back when the therapy is finished to restore the immune system. ## Harvesting The stem cells are harvested directly from the red marrow in the crest of the ilium, usually under general anesthesia. Contrary to popular belief, it is a minimally invasive outpatient procedure with only minor discomfort. Another option is to administer certain drugs that stimulate the release of stem cells from the bone marrow into circulating blood. An IV is inserted into the donor's arm, and the stem cells are filtered out of the blood. The procedure is similar to donating blood or platelets. It may also be taken from the sternum. The tibia may seem a good source, since it is very superficial. However, except in children, this bonemarrow doesn't contain any substantial amount of red bone marrow, but rather only yellow bone marrow. [1] In newborns, stem cells may be retrieved from the umbilical cord. # Bone marrow: Metastatic Adenocarcinoma # Bone marrow as a food Though once used in various preparations, including pemmican, bone marrow for human consumption in America has recently fallen out of favor as a food. Now, it is commonly used only as a flavoring for soups and sauces, although dishes with intact bone marrow can still be found in some European restaurants. Bone marrow is a source of protein and high in monounsaturated fats. These fats are known to decrease LDL cholesterol levels resulting in a reduced risk of cardiovascular disease, prompting some to make bone marrow a dietary staple. The actual health effects of the addition of bone marrow to the diet remain unclear.	https://www.wikidoc.org/index.php/Bone_Marrow_Transplantation
155db541dcc3ab50b1b7856cf383df7a91fb5ba5	wikidoc	Bone island	Bone island Synonyms and keywords: Enostosis # Overview - A bone island is a focus of compact bone located in cancellous bone. - Benign entity that is usually found incidentally on imaging studies - Histologically, bone islands are intramedullary foci of normal compact bone with haversian canals and "thorny" radiations that merge with the trabeculae of surrounding normal cancellous bone. - Most commonly identified in the pelvis, long bones, ribs, and spine. # Diagnosis ## X-ray - Round or ovoid intramedullary sclerotic foci. - Long axis of a bone island typically parallels the long axis of the involved bone. Bone islands appear homogeneously sclerotic with “thorny” radiating bone spicules that extend from the center of the lesion and blend with the trabeculae. ## CT - Same as above for plain films ## MRI - Dark on all pulse sequences	Bone island Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Synonyms and keywords: Enostosis # Overview - A bone island is a focus of compact bone located in cancellous bone. - Benign entity that is usually found incidentally on imaging studies - Histologically, bone islands are intramedullary foci of normal compact bone with haversian canals and "thorny" radiations that merge with the trabeculae of surrounding normal cancellous bone. - Most commonly identified in the pelvis, long bones, ribs, and spine. # Diagnosis ## X-ray - Round or ovoid intramedullary sclerotic foci. - Long axis of a bone island typically parallels the long axis of the involved bone. Bone islands appear homogeneously sclerotic with “thorny” radiating bone spicules that extend from the center of the lesion and blend with the trabeculae. ## CT - Same as above for plain films ## MRI - Dark on all pulse sequences - - -	https://www.wikidoc.org/index.php/Bone_island
8f74053a5fd6d66d05f8685111f126273516ada4	wikidoc	Borborygmus	Borborygmus # Overview Borborygmus (plural borborygmi) (from Greek βορβορυγμός) is the rumbling sound produced by the movement of gas through the intestines of animals or humans. The word borborygmus is an onomatopoeia for this rumbling. The "rumble" or "growl" sometimes heard from the stomach is a normal part of digestion. It originates in the stomach or upper part of the small intestine as muscles contract to move food and digestive juices down the gastrointestinal tract and functions as a sort of intestinal "housecleaning". Sometimes it occurs as part of the Migrating Myoelectric Complex. Although this muscle contraction happens whether or not food is present, rumbles are more common after the animal has gone several hours without eating. This may be why a "growling" stomach is often associated with hunger. Rumbles may also occur when there is incomplete digestion of food that can lead to excess gas in the intestine. In humans this can be due to incomplete digestion of carbohydrate-containing foods including milk and other dairy products (lactose intolerance or the use of α-glucosidase inhibitors by diabetics), gluten (protein in wheat, barley, and rye) (celiac disease), fruits, vegetables, beans, legumes, and high-fiber whole grains. In rare instances, excessive abdominal noise may be a sign of digestive disease, especially when accompanied by abdominal bloating, abdominal pain, diarrhea or constipation. An example of a disease that may be associated with this symptom are carcinoid tumors.	Borborygmus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Borborygmus (plural borborygmi) (from Greek βορβορυγμός) is the rumbling sound produced by the movement of gas through the intestines of animals or humans. The word borborygmus is an onomatopoeia for this rumbling.[1] The "rumble" or "growl" sometimes heard from the stomach is a normal part of digestion. It originates in the stomach or upper part of the small intestine as muscles contract to move food and digestive juices down the gastrointestinal tract and functions as a sort of intestinal "housecleaning". Sometimes it occurs as part of the Migrating Myoelectric Complex. Although this muscle contraction happens whether or not food is present, rumbles are more common after the animal has gone several hours without eating. This may be why a "growling" stomach is often associated with hunger. Rumbles may also occur when there is incomplete digestion of food that can lead to excess gas in the intestine. In humans this can be due to incomplete digestion of carbohydrate-containing foods including milk and other dairy products (lactose intolerance or the use of α-glucosidase inhibitors by diabetics), gluten (protein in wheat, barley, and rye) (celiac disease), fruits, vegetables, beans, legumes, and high-fiber whole grains. In rare instances, excessive abdominal noise may be a sign of digestive disease, especially when accompanied by abdominal bloating, abdominal pain, diarrhea or constipation. An example of a disease that may be associated with this symptom are carcinoid tumors.	https://www.wikidoc.org/index.php/Borborygmi
6b74ba4a1410ac18b5ce7ee9177af6cdd211f90d	wikidoc	Borkum Riff	Borkum Riff Borkum Riff is a brand of pipe tobacco manufactured in Denmark by Swedish Match. Borkum Riff is one of the most popular brands in th world and was launched in 1968. # The History of Borkum Riff During the Age of Discovery the first Swedish explorers travelled to North America. Arriving in Delaware in 1638, they rapidly established a permanent colony and began trading with the local inhabitants who were eager to barter items such as furs in exchange for goods from Sweden. It soon became apparent that one of these locally produced items, tobacco, had great appeal in Europe. Taking advantage of this opportunity, Queen Kristina of Sweden appointed skilled craftsmen to refine the art of producing fine pipe tobacco for the Europe's nobility. This tradition has been kept alive by Borkum Riff which has gained a well-deserved reputation for excellence among connoisseurs of pipe tobacco around the world. The story of Borkum Riff starts at the beginning of the 1960’s when a pipe tobacco was launched on the Swedish market under the brand name of Borkum Riff. Prior to 1960, the name 'Borkum Riff' was only known as a lighthouse located at 53° 58' N, and 6° 22' E in the Helgoland Bay off the Dutch coast in the North Sea. This lighthouse was a landmark for seafaring men and was well-known to Swedish radio listeners, as weather reports mentioned Borkum Riff several times a day. The tobacco launched in Sweden under the Borkum Riff name was a rough cut mixture of a blend of Virginia and Burley tobaccos. It got off to a slow start but sales increased gradually. However, it was not until the whiskey flavour was added that sales began to soar. Today, the Borkum Riff brand is the third largest on the Swedish market, after the leading Greve Hamilton and Caravelle. Late in 1968, a new chapter started in the history of Borkum Riff. This was the year when tobacco blenders at the Swedish Tobacco Co created the formula for a new pipe tobacco with unique smoking characteristics – a revolution for the world’s smoking public. The tobacco blend developed was soft and rich yet mellow in taste. It did not bite or hurt the mouth, was easy to handle and to keep lit. It was lightly flavoured, yet sufficiently strong to provide taste and create an agreeable aroma. The tobacco turned out to be the perfect choice for those wishing to switch from cigarette smoking to pipe smoking and immediately became a great worldwide success. It is, however, not enough to have a unique pipe tobacco blend of high quality. The package must reflect the high quality image, and the Borkum Riff pouch package already on the Swedish market was the obvious choice. The design of the Borkum Riff package is unique in its simplicity. It is timeless with many interesting individual design elements. The ship in the design originates from a 17th century engraving made by Johann Baptista Homann, who lived in Germany. The tobacco blend had, of course, been developed with an eye on the world’s largest pipe tobacco market, i.e. the US. Borkum Riff, the Bourbon Whiskey blend, was introduced in the US in 1969 and a major success was achieved. It was not difficult to sell in Borkum Riff on the US market. At an early stage very favourable comments were received from wholesale- and retail trades as well as from consumers. It was even said that this was the pipe tobacco that US pipe smokers had been longing for. Since then new flavours and new packaging formats have been introduced. Borkum Riff has, of course, not only been spread on the US market but on markets such as Canada, Australia, Switzerland, Spain, New Zealand, Japan, France, Italy, Germany as well as on several other markets all around the world. Borkum Riff's biggest market is the United States. There is no doubt whatsoever that Borkum Riff is one of today’s greatest tobacco successes in the world. As of 2007 there are several products: - Borkum Riff Original - Borkum Riff Bourbon Whisky - Borkum Riff Cherry Liqueur - Borkum Riff Scandinavian Mixture - Borkum Riff Orange & Honey - Borkum Riff Cherry Cavendish - Borkum Riff Black Cavendish - Borkum Riff Vanilla Cavendish - Borkum Riff Champagne - Borkum Riff Highland Malt Whiskey - Borkum Riff Special Mixture No. 8 - Borkum Riff GOLD Cherry & Vanilla - Borkum Riff GOLD Malt Whiskey - Borkum Riff Admiral's Flake Vanilla - Borkum Riff Admiral's Flake Cherry - Borkum Riff French Vanilla	Borkum Riff Template:Advert Borkum Riff is a brand of pipe tobacco manufactured in Denmark by Swedish Match. Borkum Riff is one of the most popular brands in th world and was launched in 1968. # The History of Borkum Riff During the Age of Discovery the first Swedish explorers travelled to North America. Arriving in Delaware in 1638, they rapidly established a permanent colony and began trading with the local inhabitants who were eager to barter items such as furs in exchange for goods from Sweden. It soon became apparent that one of these locally produced items, tobacco, had great appeal in Europe. Taking advantage of this opportunity, Queen Kristina of Sweden appointed skilled craftsmen to refine the art of producing fine pipe tobacco for the Europe's nobility. This tradition has been kept alive by Borkum Riff which has gained a well-deserved reputation for excellence among connoisseurs of pipe tobacco around the world. The story of Borkum Riff starts at the beginning of the 1960’s when a pipe tobacco was launched on the Swedish market under the brand name of Borkum Riff. Prior to 1960, the name 'Borkum Riff' was only known as a lighthouse located at 53° 58' N, and 6° 22' E in the Helgoland Bay off the Dutch coast in the North Sea. This lighthouse was a landmark for seafaring men and was well-known to Swedish radio listeners, as weather reports mentioned Borkum Riff several times a day. The tobacco launched in Sweden under the Borkum Riff name was a rough cut mixture of a blend of Virginia and Burley tobaccos. It got off to a slow start but sales increased gradually. However, it was not until the whiskey flavour was added that sales began to soar. Today, the Borkum Riff brand is the third largest on the Swedish market, after the leading Greve Hamilton and Caravelle. Late in 1968, a new chapter started in the history of Borkum Riff. This was the year when tobacco blenders at the Swedish Tobacco Co created the formula for a new pipe tobacco with unique smoking characteristics – a revolution for the world’s smoking public. The tobacco blend developed was soft and rich yet mellow in taste. It did not bite or hurt the mouth, was easy to handle and to keep lit. It was lightly flavoured, yet sufficiently strong to provide taste and create an agreeable aroma. The tobacco turned out to be the perfect choice for those wishing to switch from cigarette smoking to pipe smoking and immediately became a great worldwide success. It is, however, not enough to have a unique pipe tobacco blend of high quality. The package must reflect the high quality image, and the Borkum Riff pouch package already on the Swedish market was the obvious choice. The design of the Borkum Riff package is unique in its simplicity. It is timeless with many interesting individual design elements. The ship in the design originates from a 17th century engraving made by Johann Baptista Homann, who lived in Germany. The tobacco blend had, of course, been developed with an eye on the world’s largest pipe tobacco market, i.e. the US. Borkum Riff, the Bourbon Whiskey blend, was introduced in the US in 1969 and a major success was achieved. It was not difficult to sell in Borkum Riff on the US market. At an early stage very favourable comments were received from wholesale- and retail trades as well as from consumers. It was even said that this was the pipe tobacco that US pipe smokers had been longing for. Since then new flavours and new packaging formats have been introduced. Borkum Riff has, of course, not only been spread on the US market but on markets such as Canada, Australia, Switzerland, Spain, New Zealand, Japan, France, Italy, Germany as well as on several other markets all around the world. Borkum Riff's biggest market is the United States. There is no doubt whatsoever that Borkum Riff is one of today’s greatest tobacco successes in the world. As of 2007 there are several products: - Borkum Riff Original - Borkum Riff Bourbon Whisky - Borkum Riff Cherry Liqueur - Borkum Riff Scandinavian Mixture - Borkum Riff Orange & Honey - Borkum Riff Cherry Cavendish - Borkum Riff Black Cavendish - Borkum Riff Vanilla Cavendish - Borkum Riff Champagne - Borkum Riff Highland Malt Whiskey - Borkum Riff Special Mixture No. 8 - Borkum Riff GOLD Cherry & Vanilla - Borkum Riff GOLD Malt Whiskey - Borkum Riff Admiral's Flake Vanilla - Borkum Riff Admiral's Flake Cherry - Borkum Riff French Vanilla # External links - Borkum Riff web site - Swedish Match web site sv:Borkum Riff	https://www.wikidoc.org/index.php/Borkum_Riff
75c11a1ac84002ac4f2d7441cb144cae3153a813	wikidoc	Boron group	Boron group The boron group is the series of elements in group 13 (IUPAC style) in the periodic table. The group has previously also been referred to as the earth metals and the triels, from the Latin tri, three, stemming from the naming convention of this group as Group IIIB. These elements are characterized by having three electrons in their outer energy levels (valence layers). Boron is considered a metalloid, and the rest are considered metals of the poor metals groups. The boron group consists of boron (B), aluminium (Al), gallium (Ga), indium (In), thallium (Tl), and ununtrium (Uut) (unconfirmed). Boron occurs sparsely probably because of disruption of its nucleus by bombardment with subatomic particles produced from natural radioactivity. Aluminum occurs widely on earth and in fact, it is the third most abundant element in the earth's crust (7.4%). ar:مجموعة بورون ast:Elementos del grupu 13 ca:Grup del bor cs:Triely de:Borgruppe eo:Elemento de grupo 13 ko:13족 원소 lmo:Grupp del bòor nl:Boorgroep nn:Gruppe 13 sr:13. група хемијских елемената sh:13. grupa hemijskih elemenata fi:Booriryhmä sv:Borgruppen th:หมู่โบรอน	Boron group The boron group is the series of elements in group 13 (IUPAC style) in the periodic table. The group has previously also been referred to as the earth metals and the triels, from the Latin tri, three, stemming from the naming convention of this group as Group IIIB. These elements are characterized by having three electrons in their outer energy levels (valence layers). Boron is considered a metalloid, and the rest are considered metals of the poor metals groups. The boron group consists of boron (B), aluminium (Al), gallium (Ga), indium (In), thallium (Tl), and ununtrium (Uut) (unconfirmed). Boron occurs sparsely probably because of disruption of its nucleus by bombardment with subatomic particles produced from natural radioactivity. Aluminum occurs widely on earth and in fact, it is the third most abundant element in the earth's crust (7.4%). Template:Inorganic-compound-stub Template:PeriodicTablesFooter ar:مجموعة بورون ast:Elementos del grupu 13 ca:Grup del bor cs:Triely de:Borgruppe eo:Elemento de grupo 13 ko:13족 원소 lmo:Grupp del bòor nl:Boorgroep nn:Gruppe 13 sr:13. група хемијских елемената sh:13. grupa hemijskih elemenata fi:Booriryhmä sv:Borgruppen th:หมู่โบรอน Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Boron_family
cb855996e24c2f833fdfa59257c1999a30c367d4	wikidoc	Bound state	Bound state In physics, a bound state is a composite of two or more building blocks (particles or bodies) that behaves as a single object. In quantum mechanics (where the number of particles is conserved), a bound state is a state in the Hilbert space that corresponds to two or more particles whose interaction energy is negative, and therefore these particles cannot be separated unless energy is spent. The energy spectrum of a bound state is discrete, unlike the continuous spectrum of isolated particles. (Actually, it is possible to have unstable bound states with a positive interaction energy provided that there is an "energy barrier" that has to be tunnelled through in order to decay. This is true for some radioactive nuclei and for some electret materials able to carry electric charge for rather long periods.) In general, a stable bound state is said to exist in a given potential of some dimension if stationary wavefunctions exist (normalized in the range of the potential). The energies of these wavefunctions are negative. In relativistic quantum field theory, a stable bound state of n particles with masses m1, ..., mn shows up as a pole in the S-matrix with a center of mass energy which is less than m1+...+mn. An unstable bound state (see resonance) shows up as a pole with a complex center of mass energy. # Examples - A proton and an electron can move separately; the total center-of-mass energy is positive, and such a pair of particles can be described as an ionized atom. Once the electron starts to "orbit" the proton, the energy becomes negative, and bound state - namely the hydrogen atom - is formed. Only the lowest energy bound state, the ground state is stable. The other excited states are unstable and will decay into bound states with less energy by emitting a photon. - A nucleus is a bound state of protons and neutrons (nucleons). - A positronium "atom" is an unstable bound state of an electron and a positron. It decays into photons. - The proton itself is a bound state of three quarks (two up and one down; one red, one green and one blue). However, unlike the case of the hydrogen atom, the individual quarks can never be isolated. See confinement.	Bound state In physics, a bound state is a composite of two or more building blocks (particles or bodies) that behaves as a single object. In quantum mechanics (where the number of particles is conserved), a bound state is a state in the Hilbert space that corresponds to two or more particles whose interaction energy is negative, and therefore these particles cannot be separated unless energy is spent. The energy spectrum of a bound state is discrete, unlike the continuous spectrum of isolated particles. (Actually, it is possible to have unstable bound states with a positive interaction energy provided that there is an "energy barrier" that has to be tunnelled through in order to decay. This is true for some radioactive nuclei and for some electret materials able to carry electric charge for rather long periods.) In general, a stable bound state is said to exist in a given potential of some dimension if stationary wavefunctions exist (normalized in the range of the potential). The energies of these wavefunctions are negative. In relativistic quantum field theory, a stable bound state of n particles with masses m1, ..., mn shows up as a pole in the S-matrix with a center of mass energy which is less than m1+...+mn. An unstable bound state (see resonance) shows up as a pole with a complex center of mass energy. # Examples - A proton and an electron can move separately; the total center-of-mass energy is positive, and such a pair of particles can be described as an ionized atom. Once the electron starts to "orbit" the proton, the energy becomes negative, and bound state - namely the hydrogen atom - is formed. Only the lowest energy bound state, the ground state is stable. The other excited states are unstable and will decay into bound states with less energy by emitting a photon. - A nucleus is a bound state of protons and neutrons (nucleons). - A positronium "atom" is an unstable bound state of an electron and a positron. It decays into photons. - The proton itself is a bound state of three quarks (two up and one down; one red, one green and one blue). However, unlike the case of the hydrogen atom, the individual quarks can never be isolated. See confinement.	https://www.wikidoc.org/index.php/Bound_state
900a1b801029ee812a64f8ffaa868a6bc5343ec8	wikidoc	Boyle's law	Boyle's law # Overview Boyle's law (sometimes referred to as the Boyle-Mariotte law) is one of the gas laws and basis of derivation for the ideal gas law, which describes the relationship between the product pressure and volume within a closed system as constant when temperature and moles remain at a fixed measure; both entities remain inversely proportional. The law was named after chemist and physicist, Robert Boyle who published the original law in 1662. The law itself can be defined succinctly as follows: # History Boyle's Law is named after the Irish natural philosopher Robert Boyle (Lismore, County Waterford, 1627-1691) who was the first to publish it in 1662. The relationship between pressure and volume was brought to the attention of Boyle by two friends and amateur scientists, Richard Towneley and Henry Power, who discovered it. Boyle confirmed their discovery through experiments and published the results. According to Robert Gunther and other authorities, Boyle's assistant Robert Hooke, who built the experimental apparatus, may well PITO have helped to quantify the law; Hooke was accounted a more able mathematician than Boyle. Hooke also developed the improved vacuum pumps necessary for the experiments. The French physicist Edme Mariotte (1620-1684) discovered the same law independently of Boyle in 1676, so this law may be referred to as Mariotte's or the Boyle-Mariotte law. # Definition ## Relation to kinetic theory and ideal gases Boyle's law states that the volume of a gas increases when the pressure decreases at a constant temperature. Also it is the most fundamental of the 23 gas laws. The law was not likely to have deviations at the time of publication due to limits upon technology, but as further technological advances occurred limitations of the approach would have become known, as Boyle's law relates more effectively to real gases due to its description of such gases consisting of large numbers of particles moving independently of each other. In 1738, Daniel Bernoulli derived Boyle's law using Newton's laws of motion with application on a molecular level, but remained ignored until c. 1845, when John Waterston published a paper building the main precepts of kinetic theory, but was rejected by the Royal Society of England until the later works of James Prescott Joule, Rudolf Clausius and Ludwig Boltzmann firmly established the kinetic theory of gases and brought attention to both the theories of Bernoulli and Waterston. The ongoing debate between proponents of Energetics and Atomism led Boltzmann to write a book in 1898, which endured criticism up to his suicide in 1901. Albert Einstein in 1905 showed how kinetic theory applied to the Brownian motion of a fluid-suspended particle, which was confirmed in 1908 by Jean Perrin. From these perspectives upon kinetic theory, the derivation of Boyle's Law can be achieved through its assumptions. ## Equation The mathematical equation for Boyle's law is: where: So long as temperature remains constant at the same value the same amount of energy given to the system persists throughout its operation and therefore, theoretically, the value of k will remain constant. However, due to the derivation of pressure as perpendicular applied force and the probabilistic likelihood of collisions with other particles through collision theory, the application of force to a surface may not be infinitely constant for such values of k, but will have a limit when differentiating such values over a given time. Forcing the volume V of the fixed quantity of gas to increase, keeping the gas at the initially measured temperature, the pressure p must decrease proportionally. Conversely, reducing the volume of the gas increases the pressure. Boyle's law is commonly used to predict the result of introducing a change, in volume and pressure only, to the initial state of a fixed quantity of gas. The "before" and "after" volumes and pressures of the fixed amount of gas, where the "before" and "after" temperatures are the same (heating or cooling will be required to meet this condition), are related by the equation: Boyle's law, Charles' law, and Gay-Lussac's Law form the combined gas law. The three gas laws in combination with Avogadro's law can be generalized by the ideal gas law.	Boyle's law Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Boyle's law (sometimes referred to as the Boyle-Mariotte law) is one of the gas laws and basis of derivation for the ideal gas law, which describes the relationship between the product pressure and volume within a closed system as constant when temperature and moles remain at a fixed measure; both entities remain inversely proportional.[1][2] The law was named after chemist and physicist, Robert Boyle who published the original law in 1662. The law itself can be defined succinctly as follows: # History Boyle's Law is named after the Irish natural philosopher Robert Boyle (Lismore, County Waterford, 1627-1691) who was the first to publish it in 1662. The relationship between pressure and volume was brought to the attention of Boyle by two friends and amateur scientists, Richard Towneley and Henry Power, who discovered it. Boyle confirmed their discovery through experiments and published the results. According to Robert Gunther and other authorities, Boyle's assistant Robert Hooke, who built the experimental apparatus, may well PITO have helped to quantify the law; Hooke was accounted a more able mathematician than Boyle. Hooke also developed the improved vacuum pumps necessary for the experiments. The French physicist Edme Mariotte (1620-1684) discovered the same law independently of Boyle in 1676, so this law may be referred to as Mariotte's or the Boyle-Mariotte law. # Definition ## Relation to kinetic theory and ideal gases Boyle's law states that the volume of a gas increases when the pressure decreases at a constant temperature. Also it is the most fundamental of the 23 gas laws. The law was not likely to have deviations at the time of publication due to limits upon technology, but as further technological advances occurred limitations of the approach would have become known, as Boyle's law relates more effectively to real gases[3] due to its description of such gases consisting of large numbers of particles moving independently of each other.[3] In 1738, Daniel Bernoulli derived Boyle's law using Newton's laws of motion with application on a molecular level, but remained ignored until c. 1845, when John Waterston published a paper building the main precepts of kinetic theory, but was rejected by the Royal Society of England until the later works of James Prescott Joule, Rudolf Clausius and Ludwig Boltzmann firmly established the kinetic theory of gases and brought attention to both the theories of Bernoulli and Waterston.[4] The ongoing debate between proponents of Energetics and Atomism led Boltzmann to write a book in 1898, which endured criticism up to his suicide in 1901.[4] Albert Einstein in 1905 showed how kinetic theory applied to the Brownian motion of a fluid-suspended particle, which was confirmed in 1908 by Jean Perrin.[4] From these perspectives upon kinetic theory, the derivation of Boyle's Law can be achieved through its assumptions. ## Equation The mathematical equation for Boyle's law is: where: So long as temperature remains constant at the same value the same amount of energy given to the system persists throughout its operation and therefore, theoretically, the value of k will remain constant. However, due to the derivation of pressure as perpendicular applied force and the probabilistic likelihood of collisions with other particles through collision theory, the application of force to a surface may not be infinitely constant for such values of k, but will have a limit when differentiating such values over a given time. Forcing the volume V of the fixed quantity of gas to increase, keeping the gas at the initially measured temperature, the pressure p must decrease proportionally. Conversely, reducing the volume of the gas increases the pressure. Boyle's law is commonly used to predict the result of introducing a change, in volume and pressure only, to the initial state of a fixed quantity of gas. The "before" and "after" volumes and pressures of the fixed amount of gas, where the "before" and "after" temperatures are the same (heating or cooling will be required to meet this condition), are related by the equation: Boyle's law, Charles' law, and Gay-Lussac's Law form the combined gas law. The three gas laws in combination with Avogadro's law can be generalized by the ideal gas law.	https://www.wikidoc.org/index.php/Boyle%27s_Law
dc54386adf137fd81c75db138d758de55bbcf118	wikidoc	Encorafenib	Encorafenib # 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 Encorafenib is a kinase inhibitor that is FDA approved for the treatment of patients, in combination with binimetinib, with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Common adverse reactions include fatigue, nausea, vomiting, abdominal pain, and arthralgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Encorafenib is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Limitations of Use - Encorafenib is not indicated for treatment of patients with wild-type BRAF melanoma. Dosage - The recommended dose is 450 mg orally once daily in combination with binimetinib. Take encorafenib with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding encorafenib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding encorafenib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of encorafenib have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding encorafenib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding encorafenib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib. Cutaneous Malignancies - In COLUMBUS, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received encorafenib in combination with binimetinib. Median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months). - For patients who received encorafenib as a single agent, cuSCC/KA was reported in 8%, basal cell carcinoma in 1%, and a new primary melanoma in 5% of patients. - Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Non-Cutaneous Malignancies - Based on its mechanism of action, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving encorafenib for signs and symptoms of non-cutaneous malignancies. Discontinue encorafenib for RAS mutation-positive non-cutaneous malignancies. - In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating encorafenib. - Hemorrhage can occur when encorafenib is administered in combination with binimetinib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving encorafenib in combination with binimetinib; Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. - Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Uveitis, including iritis and iridocyclitis, has been reported in patients treated with encorafenib in combination with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with encorafenib in combination with binimetinib was 4%. - Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Encorafenib is associated with dose-dependent QTc interval prolongation in some patients. In COLUMBUS, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients who received encorafenib in combination with binimetinib. - Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during encorafenib administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms. - Based on its mechanism of action, encorafenib can cause fetal harm when administered to a pregnant woman. Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses. - Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective, non-hormonal method of contraception since encorafenib can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the final dose of encorafenib. - Encorafenib when used as a single agent is associated with an increased risk of certain adverse reactions compared to when encorafenib is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with encorafenib single agent compared to 2% of patients treated with encorafenib in combination with binimetinib. - If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of encorafenib as recommended. - Encorafenib is indicated for use in combination with binimetinib. Refer to the binimetinib prescribing information for additional risk information that applies to combination use treatment. # 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 encorafenib in combination with binimetinib is described in 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received encorafenib (450 mg once daily) in combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial (COLUMBUS). - The COLUMBUS trial excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with encorafenib in combination with binimetinib and 6.2 months for patients treated with vemurafenib. - The most common (≥ 25%) adverse reactions in patients receiving encorafenib in combination with binimetinib were fatigue, nausea, vomiting, abdominal pain, and arthralgia. - Adverse reactions leading to dose interruptions of encorafenib occurred in 30% of patients receiving encorafenib in combination with binimetinib; the most common were nausea (7%), vomiting (7%) and pyrexia (4%). Adverse reactions leading to dose reductions of encorafenib occurred in 14% of patients receiving encorafenib in combination with binimetinib; the most common were arthralgia (2%), fatigue (2%) and nausea (2%). Five percent (5%) of patients receiving encorafenib in combination with binimetinib experienced an adverse reaction that resulted in permanent discontinuation of encorafenib; the most common were hemorrhage in 2% and headache in 1% of patients. - Table 4 and Table 5 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for encorafenib in combination with binimetinib, as compared to vemurafenib, for any specific adverse reaction listed in Table 4. - Encorafenib when used as a single agent increases the risk of certain adverse reactions compared to encorafenib in combination with binimetinib. In patients receiving encorafenib 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate (≥ 5%) compared to patients receiving encorafenib in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%). - Other clinically important adverse reactions occurring in < 10% of patients who received encorafenib in combination with binimetinib were: Nervous system disorders: Facial paresis Gastrointestinal disorders: Pancreatitis Skin and subcutaneous tissue disorders: Panniculitis Immune system disorders: Drug hypersensitivity - Nervous system disorders: Facial paresis - Gastrointestinal disorders: Pancreatitis - Skin and subcutaneous tissue disorders: Panniculitis - Immune system disorders: Drug hypersensitivity ## Postmarketing Experience There is limited information regarding Encorafenib Postmarketing Experience in the drug label. # Drug Interactions Strong or Moderate CYP3A4 Inhibitors - Concomitant administration of encorafenib with a strong or moderate CYP3A4 inhibitor increased encorafenib plasma concentrations and may increase encorafenib adverse reactions. Avoid coadministration of encorafenib with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration of strong or moderate CYP3A4 inhibitors cannot be avoided, modify dose as recommended. Strong or Moderate CYP3A4 Inducers - Concomitant administration of encorafenib with a strong or moderate CYP3A4 inducer may decrease encorafenib plasma concentrations and may decrease encorafenib efficacy. Avoid concomitant administration of strong or moderate CYP3A4 inducers with encorafenib. Sensitive CYP3A4 Substrates - Concomitant administration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents. - Coadministration of encorafenib with hormonal contraceptives (CYP3A4 substrates) can result in decreased concentrations and loss of hormonal contraceptive efficacy. Avoid hormonal contraceptives. - Encorafenib is associated with dose-dependent QTc interval prolongation. Avoid coadministration of encorafenib with medicinal products with a known potential to prolong QT/QTc interval. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on its mechanism of action, encorafenib can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of encorafenib during pregnancy. In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses. Advise pregnant women of the potential risk to a fetus. - 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. Animal Data - In reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at a dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentration-time curve at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at a dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Encorafenib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Encorafenib during labor and delivery. ### Nursing Mothers Risk Summary - There are no data on the presence of encorafenib or its metabolites in human milk or the effects of encorafenib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from encorafenib in breastfed infants, advise women not to breastfeed during treatment with encorafenib and for 2 weeks after the final dose. ### Pediatric Use - The safety and effectiveness of encorafenib have not been established in pediatric patients. ### Geriatic Use - Of the 690 patients with BRAF mutation-positive melanoma who received encorafenib at doses between 300 mg and 600 mg once daily in combination with binimetinib (45 mg twice daily) across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in the safety or effectiveness of encorafenib plus binimetinib were observed in elderly patients as compared to younger patients. ### Gender There is no FDA guidance on the use of Encorafenib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Encorafenib with respect to specific racial populations. ### Renal Impairment - No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min). A recommended dose has not been established for patients with severe renal impairment (CLcr < 30 mL/min). ### Hepatic Impairment - Dose adjustment for encorafenib is not recommended in patients with mild hepatic impairment (Child-Pugh Class A). A recommended dose has not been established for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. ### Females of Reproductive Potential and Males Pregnancy Testing - Verify the pregnancy status of females of reproductive potential prior to initiating encorafenib. Contraception - Encorafenib can cause fetal harm when administered to a pregnant woman - Advise females of reproductive potential to use effective contraception during treatment with encorafenib and for 2 weeks after the final dose. Counsel patients to use a non-hormonal method of contraception since encorafenib has the potential to render hormonal contraceptives ineffective. Infertility - Based on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose, use of encorafenib may impact fertility in males. ### Immunocompromised Patients There is no FDA guidance one the use of Encorafenib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating encorafenib. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: . - The recommended dosage of encorafenib is 450 mg (six 75 mg capsules) orally taken once daily in combination with binimetinib until disease progression or unacceptable toxicity. Refer to the binimetinib prescribing information for recommended binimetinib dosing information. - Encorafenib may be taken with or without food. Do not take a missed dose of encorafenib within 12 hours of the next dose of encorafenib. - Do not take an additional dose if vomiting occurs after encorafenib administration but continue with the next scheduled dose. - If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 mg once daily until binimetinib is resumed. - Dose reductions for adverse reactions associated with encorafenib are presented in Table 1. - Dosage modifications for adverse reactions associated with encorafenib are presented in Table 2. - Refer to the binimetinib prescribing information for dose modifications for adverse reactions associated with binimetinib. - Avoid coadministration with strong or moderate CYP3A4 inhibitors during treatment with encorafenib. If coadministration with a strong or moderate CYP3A4 inhibitor is unavoidable, reduce the encorafenib dose according to the recommendations in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor. ### Monitoring There is limited information regarding Encorafenib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Encorafenib and IV administrations. # Overdosage - Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with encorafenib. # Pharmacology ## Mechanism of Action - Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and substantially reduce ligand binding to these kinases at clinically achievable concentrations (≤ 0.9 µM). - Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression. - Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. ## Structure - The molecular formula is C22H27ClFN7O4S and the molecular weight is 540 daltons. The chemical structure of encorafenib is shown below: ## Pharmacodynamics Cardiac Electrophysiology - A dedicated study to evaluate the QT prolongation potential of encorafenib has not been conducted. Encorafenib is associated with dose-dependent QTc interval prolongation. Following administration of the recommended dose of encorafenib in combination with binimetinib, based on a central tendency analysis of QTc in a study of adult patients with melanoma, the largest mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (14 to 22) ms. ## Pharmacokinetics - The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation. After a single dose, systemic exposure of encorafenib was dose proportional over the dose range of 50 mg to 700 mg. After once-daily dosing, systemic exposure of encorafenib was less than dose proportional over the dose range of 50 mg to 800 mg. Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%. Absorption - After oral administration, the median Tmax of encorafenib is 2 hours. At least 86% of the dose is absorbed. Effect of Food - Administration of a single dose of encorafenib 100 mg (0.2 times the recommended dose) with a high-fat, high-calorie meal (comprised of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) decreased the mean maximum encorafenib concentration (Cmax) by 36% with no effect on AUC. Distribution - Encorafenib is 86% bound to human plasma proteins in vitro. The blood-to-plasma concentration ratio is 0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%). Elimination - The mean (CV%) terminal half-life (t1/2) of encorafenib is 3.5 hours (17%), and the apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state. Metabolism - The primary metabolic pathway is N-dealkylation, with CYP3A4 as the main contributor (83%) to total oxidative clearance of encorafenib in human liver microsomes, followed by CYP2C19 (16%) and CYP2D6 (1%). Excretion - Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine. Specific Populations - Age (19 to 89 years), sex, body weight, mild hepatic impairment (Child-Pugh Class A), and mild or moderate renal impairment (CLcr 30 to < 90 mL/min) do not have a clinically meaningful effect on the pharmacokinetics of encorafenib. The effect of race or ethnicity, moderate or severe hepatic impairment (Child-Pugh Class B or C), and severe renal impairment (CLcr < 30 mL/min) on encorafenib pharmacokinetics have not been studied. Drug Interaction Studies Clinical Studies - Effect of CYP3A4 Inhibitors on Encorafenib: Coadministration of a strong (posaconazole) or moderate (diltiazem) CYP3A4 inhibitor with encorafenib increased the AUC of encorafenib by 3- and 2-fold, respectively, and increased the Cmax by 68% and 45%, respectively, after a single encorafenib dose of 50 mg (0.1 times the recommended dose). - Effect of CYP3A4 Inducers on Encorafenib: The effect of coadministration of a CYP3A4 inducer on encorafenib exposure has not been studied. In clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction. - Effect of Acid Reducing Agents on Encorafenib: Coadministration of a proton pump inhibitor, rabeprazole, had no effect on AUC and Cmax of encorafenib. - Combination Treatment: Coadministration of encorafenib (UGT1A1 inhibitor) with binimetinib (UGT1A1 substrate) had no effect on binimetinib exposure. In Vitro Studies - Effect of Encorafenib on CYP/UGT Substrates: Encorafenib is a reversible inhibitor of UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, and CYP3A, and a time-dependent inhibitor of CYP3A4 at clinically relevant plasma concentrations. Encorafenib induced CYP2B6, CYP2C9, and CYP3A4 at clinically relevant plasma concentrations. - Effect of Transporters on Encorafenib: Encorafenib is a substrate of P-glycoprotein (P-gp). Encorafenib is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), organic anion transporting polypeptide (OATP1B1, OATP1B3) or organic cation transporter (OCT1) at clinically relevant plasma concentrations. - Effect of Encorafenib on Transporters: Encorafenib inhibited P-gp, BCRP, OCT2, organic anion transporter (OAT1, OAT3), OATP1B1, and OATP1B3, but not OCT1 or MRP2 at clinically relevant plasma concentrations. ## Nonclinical Toxicology - Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats. - No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the non-human primate toxicity studies. - Adverse histopathology findings of hyperplasia and hyperkeratosis occurred in the stomach of rats at encorafenib doses of 20 mg/kg/day (approximately 14 times the human exposure at the 450 mg clinical dose based on AUC) or greater, in both 4 and 13-week studies. # Clinical Studies - Encorafenib in combination with binimetinib was evaluated in a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no). - Patients were randomized (1:1:1) to receive encorafenib 450 mg once daily in combination with binimetinib 45 mg twice daily (encorafenib in combination with binimetinib), encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (encorafenib 450 mg in combination with binimetinib 45 mg) are described below. - The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent central review, to compare encorafenib in combination with binimetinib with vemurafenib. Additional efficacy outcome measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review. - A total of 577 patients were randomized, 192 to the encorafenib in combination with binimetinib arm, 194 to the encorafenib arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the encorafenib in combination with binimetinib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had ≥ 3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients' tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (<1%). - Encorafenib in combination with binimetinib demonstrated a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 6 and Figure 1. # How Supplied - Encorafenib is supplied as 75 mg hard gelatin capsules. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) . Do not use if safety seal under cap is broken or missing. Dispense in original bottle. Do not remove desiccant. Protect from moisture. Keep container tightly closed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). - Inform patients of the following: New Primary Cutaneous Malignancies - Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions. Hemorrhage - Advise patients to notify their healthcare provider immediately with any symptoms suggestive of hemorrhage, such as unusual bleeding. Uveitis - Advise patients to contact their healthcare provider if they experience any changes in their vision. QT Prolongation - Advise patients that encorafenib can cause QTc interval prolongation and to inform their physician if they have any QTc interval prolongation symptoms, such as syncope. Females and Males of Reproductive Potential - Embryo-Fetal Toxicity: Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with encorafenib and for 2 weeks after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with encorafenib. - Lactation: Advise women not to breastfeed during treatment with encorafenib and for 2 weeks after the final dose. - Infertility: Advise males of reproductive potential that encorafenib may impair fertility. Strong or Moderate CYP3A Inducers or Inhibitors - Coadministration of encorafenib with a strong or moderate CYP3A inhibitor may increase encorafenib concentrations; while coadministration of encorafenib with a strong or moderate CYP3A inducer may decrease encorafenib concentrations. Advise patients that they need to avoid certain medications while taking encorafenib and to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit or grapefruit juice while taking encorafenib. Storage - Encorafenib is moisture sensitive. Advise patients to store encorafenib in the original bottle with desiccant and to keep the cap of the bottle tightly closed. Do not remove the desiccants from the bottle. # Precautions with Alcohol Alcohol-Encorafenib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Braftovi # Look-Alike Drug Names There is limited information regarding Encorafenib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Encorafenib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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 Encorafenib is a kinase inhibitor that is FDA approved for the treatment of patients, in combination with binimetinib, with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Common adverse reactions include fatigue, nausea, vomiting, abdominal pain, and arthralgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Encorafenib is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. Limitations of Use - Encorafenib is not indicated for treatment of patients with wild-type BRAF melanoma. Dosage - The recommended dose is 450 mg orally once daily in combination with binimetinib. Take encorafenib with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding encorafenib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding encorafenib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of encorafenib have not been established in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding encorafenib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding encorafenib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib. Cutaneous Malignancies - In COLUMBUS, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received encorafenib in combination with binimetinib. Median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months). - For patients who received encorafenib as a single agent, cuSCC/KA was reported in 8%, basal cell carcinoma in 1%, and a new primary melanoma in 5% of patients. - Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Non-Cutaneous Malignancies - Based on its mechanism of action, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving encorafenib for signs and symptoms of non-cutaneous malignancies. Discontinue encorafenib for RAS mutation-positive non-cutaneous malignancies. - In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating encorafenib. - Hemorrhage can occur when encorafenib is administered in combination with binimetinib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving encorafenib in combination with binimetinib; Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. - Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Uveitis, including iritis and iridocyclitis, has been reported in patients treated with encorafenib in combination with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with encorafenib in combination with binimetinib was 4%. - Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. - Encorafenib is associated with dose-dependent QTc interval prolongation in some patients. In COLUMBUS, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients who received encorafenib in combination with binimetinib. - Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during encorafenib administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms. - Based on its mechanism of action, encorafenib can cause fetal harm when administered to a pregnant woman. Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses. - Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective, non-hormonal method of contraception since encorafenib can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the final dose of encorafenib. - Encorafenib when used as a single agent is associated with an increased risk of certain adverse reactions compared to when encorafenib is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with encorafenib single agent compared to 2% of patients treated with encorafenib in combination with binimetinib. - If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of encorafenib as recommended. - Encorafenib is indicated for use in combination with binimetinib. Refer to the binimetinib prescribing information for additional risk information that applies to combination use treatment. # 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 encorafenib in combination with binimetinib is described in 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received encorafenib (450 mg once daily) in combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial (COLUMBUS). - The COLUMBUS trial excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with encorafenib in combination with binimetinib and 6.2 months for patients treated with vemurafenib. - The most common (≥ 25%) adverse reactions in patients receiving encorafenib in combination with binimetinib were fatigue, nausea, vomiting, abdominal pain, and arthralgia. - Adverse reactions leading to dose interruptions of encorafenib occurred in 30% of patients receiving encorafenib in combination with binimetinib; the most common were nausea (7%), vomiting (7%) and pyrexia (4%). Adverse reactions leading to dose reductions of encorafenib occurred in 14% of patients receiving encorafenib in combination with binimetinib; the most common were arthralgia (2%), fatigue (2%) and nausea (2%). Five percent (5%) of patients receiving encorafenib in combination with binimetinib experienced an adverse reaction that resulted in permanent discontinuation of encorafenib; the most common were hemorrhage in 2% and headache in 1% of patients. - Table 4 and Table 5 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for encorafenib in combination with binimetinib, as compared to vemurafenib, for any specific adverse reaction listed in Table 4. - Encorafenib when used as a single agent increases the risk of certain adverse reactions compared to encorafenib in combination with binimetinib. In patients receiving encorafenib 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate (≥ 5%) compared to patients receiving encorafenib in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%). - Other clinically important adverse reactions occurring in < 10% of patients who received encorafenib in combination with binimetinib were: Nervous system disorders: Facial paresis Gastrointestinal disorders: Pancreatitis Skin and subcutaneous tissue disorders: Panniculitis Immune system disorders: Drug hypersensitivity - Nervous system disorders: Facial paresis - Gastrointestinal disorders: Pancreatitis - Skin and subcutaneous tissue disorders: Panniculitis - Immune system disorders: Drug hypersensitivity ## Postmarketing Experience There is limited information regarding Encorafenib Postmarketing Experience in the drug label. # Drug Interactions Strong or Moderate CYP3A4 Inhibitors - Concomitant administration of encorafenib with a strong or moderate CYP3A4 inhibitor increased encorafenib plasma concentrations and may increase encorafenib adverse reactions. Avoid coadministration of encorafenib with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration of strong or moderate CYP3A4 inhibitors cannot be avoided, modify dose as recommended. Strong or Moderate CYP3A4 Inducers - Concomitant administration of encorafenib with a strong or moderate CYP3A4 inducer may decrease encorafenib plasma concentrations and may decrease encorafenib efficacy. Avoid concomitant administration of strong or moderate CYP3A4 inducers with encorafenib. Sensitive CYP3A4 Substrates - Concomitant administration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents. - Coadministration of encorafenib with hormonal contraceptives (CYP3A4 substrates) can result in decreased concentrations and loss of hormonal contraceptive efficacy. Avoid hormonal contraceptives. - Encorafenib is associated with dose-dependent QTc interval prolongation. Avoid coadministration of encorafenib with medicinal products with a known potential to prolong QT/QTc interval. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on its mechanism of action, encorafenib can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of encorafenib during pregnancy. In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses. Advise pregnant women of the potential risk to a fetus. - 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. Animal Data - In reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at a dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentration-time curve [AUC] at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at a dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Encorafenib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Encorafenib during labor and delivery. ### Nursing Mothers Risk Summary - There are no data on the presence of encorafenib or its metabolites in human milk or the effects of encorafenib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from encorafenib in breastfed infants, advise women not to breastfeed during treatment with encorafenib and for 2 weeks after the final dose. ### Pediatric Use - The safety and effectiveness of encorafenib have not been established in pediatric patients. ### Geriatic Use - Of the 690 patients with BRAF mutation-positive melanoma who received encorafenib at doses between 300 mg and 600 mg once daily in combination with binimetinib (45 mg twice daily) across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in the safety or effectiveness of encorafenib plus binimetinib were observed in elderly patients as compared to younger patients. ### Gender There is no FDA guidance on the use of Encorafenib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Encorafenib with respect to specific racial populations. ### Renal Impairment - No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min). A recommended dose has not been established for patients with severe renal impairment (CLcr < 30 mL/min). ### Hepatic Impairment - Dose adjustment for encorafenib is not recommended in patients with mild hepatic impairment (Child-Pugh Class A). A recommended dose has not been established for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. ### Females of Reproductive Potential and Males Pregnancy Testing - Verify the pregnancy status of females of reproductive potential prior to initiating encorafenib. Contraception - Encorafenib can cause fetal harm when administered to a pregnant woman - Advise females of reproductive potential to use effective contraception during treatment with encorafenib and for 2 weeks after the final dose. Counsel patients to use a non-hormonal method of contraception since encorafenib has the potential to render hormonal contraceptives ineffective. Infertility - Based on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose, use of encorafenib may impact fertility in males. ### Immunocompromised Patients There is no FDA guidance one the use of Encorafenib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating encorafenib. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics. - The recommended dosage of encorafenib is 450 mg (six 75 mg capsules) orally taken once daily in combination with binimetinib until disease progression or unacceptable toxicity. Refer to the binimetinib prescribing information for recommended binimetinib dosing information. - Encorafenib may be taken with or without food. Do not take a missed dose of encorafenib within 12 hours of the next dose of encorafenib. - Do not take an additional dose if vomiting occurs after encorafenib administration but continue with the next scheduled dose. - If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 mg once daily until binimetinib is resumed. - Dose reductions for adverse reactions associated with encorafenib are presented in Table 1. - Dosage modifications for adverse reactions associated with encorafenib are presented in Table 2. - Refer to the binimetinib prescribing information for dose modifications for adverse reactions associated with binimetinib. - Avoid coadministration with strong or moderate CYP3A4 inhibitors during treatment with encorafenib. If coadministration with a strong or moderate CYP3A4 inhibitor is unavoidable, reduce the encorafenib dose according to the recommendations in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor. ### Monitoring There is limited information regarding Encorafenib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Encorafenib and IV administrations. # Overdosage - Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with encorafenib. # Pharmacology ## Mechanism of Action - Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and substantially reduce ligand binding to these kinases at clinically achievable concentrations (≤ 0.9 µM). - Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression. - Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. ## Structure - The molecular formula is C22H27ClFN7O4S and the molecular weight is 540 daltons. The chemical structure of encorafenib is shown below: ## Pharmacodynamics Cardiac Electrophysiology - A dedicated study to evaluate the QT prolongation potential of encorafenib has not been conducted. Encorafenib is associated with dose-dependent QTc interval prolongation. Following administration of the recommended dose of encorafenib in combination with binimetinib, based on a central tendency analysis of QTc in a study of adult patients with melanoma, the largest mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (14 to 22) ms. ## Pharmacokinetics - The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation. After a single dose, systemic exposure of encorafenib was dose proportional over the dose range of 50 mg to 700 mg. After once-daily dosing, systemic exposure of encorafenib was less than dose proportional over the dose range of 50 mg to 800 mg. Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%. Absorption - After oral administration, the median Tmax of encorafenib is 2 hours. At least 86% of the dose is absorbed. Effect of Food - Administration of a single dose of encorafenib 100 mg (0.2 times the recommended dose) with a high-fat, high-calorie meal (comprised of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) decreased the mean maximum encorafenib concentration (Cmax) by 36% with no effect on AUC. Distribution - Encorafenib is 86% bound to human plasma proteins in vitro. The blood-to-plasma concentration ratio is 0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%). Elimination - The mean (CV%) terminal half-life (t1/2) of encorafenib is 3.5 hours (17%), and the apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state. Metabolism - The primary metabolic pathway is N-dealkylation, with CYP3A4 as the main contributor (83%) to total oxidative clearance of encorafenib in human liver microsomes, followed by CYP2C19 (16%) and CYP2D6 (1%). Excretion - Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine. Specific Populations - Age (19 to 89 years), sex, body weight, mild hepatic impairment (Child-Pugh Class A), and mild or moderate renal impairment (CLcr 30 to < 90 mL/min) do not have a clinically meaningful effect on the pharmacokinetics of encorafenib. The effect of race or ethnicity, moderate or severe hepatic impairment (Child-Pugh Class B or C), and severe renal impairment (CLcr < 30 mL/min) on encorafenib pharmacokinetics have not been studied. Drug Interaction Studies Clinical Studies - Effect of CYP3A4 Inhibitors on Encorafenib: Coadministration of a strong (posaconazole) or moderate (diltiazem) CYP3A4 inhibitor with encorafenib increased the AUC of encorafenib by 3- and 2-fold, respectively, and increased the Cmax by 68% and 45%, respectively, after a single encorafenib dose of 50 mg (0.1 times the recommended dose). - Effect of CYP3A4 Inducers on Encorafenib: The effect of coadministration of a CYP3A4 inducer on encorafenib exposure has not been studied. In clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction. - Effect of Acid Reducing Agents on Encorafenib: Coadministration of a proton pump inhibitor, rabeprazole, had no effect on AUC and Cmax of encorafenib. - Combination Treatment: Coadministration of encorafenib (UGT1A1 inhibitor) with binimetinib (UGT1A1 substrate) had no effect on binimetinib exposure. In Vitro Studies - Effect of Encorafenib on CYP/UGT Substrates: Encorafenib is a reversible inhibitor of UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, and CYP3A, and a time-dependent inhibitor of CYP3A4 at clinically relevant plasma concentrations. Encorafenib induced CYP2B6, CYP2C9, and CYP3A4 at clinically relevant plasma concentrations. - Effect of Transporters on Encorafenib: Encorafenib is a substrate of P-glycoprotein (P-gp). Encorafenib is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), organic anion transporting polypeptide (OATP1B1, OATP1B3) or organic cation transporter (OCT1) at clinically relevant plasma concentrations. - Effect of Encorafenib on Transporters: Encorafenib inhibited P-gp, BCRP, OCT2, organic anion transporter (OAT1, OAT3), OATP1B1, and OATP1B3, but not OCT1 or MRP2 at clinically relevant plasma concentrations. ## Nonclinical Toxicology - Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats. - No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the non-human primate toxicity studies. - Adverse histopathology findings of hyperplasia and hyperkeratosis occurred in the stomach of rats at encorafenib doses of 20 mg/kg/day (approximately 14 times the human exposure at the 450 mg clinical dose based on AUC) or greater, in both 4 and 13-week studies. # Clinical Studies - Encorafenib in combination with binimetinib was evaluated in a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no). - Patients were randomized (1:1:1) to receive encorafenib 450 mg once daily in combination with binimetinib 45 mg twice daily (encorafenib in combination with binimetinib), encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (encorafenib 450 mg in combination with binimetinib 45 mg) are described below. - The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent central review, to compare encorafenib in combination with binimetinib with vemurafenib. Additional efficacy outcome measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review. - A total of 577 patients were randomized, 192 to the encorafenib in combination with binimetinib arm, 194 to the encorafenib arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the encorafenib in combination with binimetinib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had ≥ 3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients' tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (<1%). - Encorafenib in combination with binimetinib demonstrated a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 6 and Figure 1. # How Supplied - Encorafenib is supplied as 75 mg hard gelatin capsules. ## Storage - Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Do not use if safety seal under cap is broken or missing. Dispense in original bottle. Do not remove desiccant. Protect from moisture. Keep container tightly closed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). - Inform patients of the following: New Primary Cutaneous Malignancies - Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions. Hemorrhage - Advise patients to notify their healthcare provider immediately with any symptoms suggestive of hemorrhage, such as unusual bleeding. Uveitis - Advise patients to contact their healthcare provider if they experience any changes in their vision. QT Prolongation - Advise patients that encorafenib can cause QTc interval prolongation and to inform their physician if they have any QTc interval prolongation symptoms, such as syncope. Females and Males of Reproductive Potential - Embryo-Fetal Toxicity: Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with encorafenib and for 2 weeks after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with encorafenib. - Lactation: Advise women not to breastfeed during treatment with encorafenib and for 2 weeks after the final dose. - Infertility: Advise males of reproductive potential that encorafenib may impair fertility. Strong or Moderate CYP3A Inducers or Inhibitors - Coadministration of encorafenib with a strong or moderate CYP3A inhibitor may increase encorafenib concentrations; while coadministration of encorafenib with a strong or moderate CYP3A inducer may decrease encorafenib concentrations. Advise patients that they need to avoid certain medications while taking encorafenib and to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit or grapefruit juice while taking encorafenib. Storage - Encorafenib is moisture sensitive. Advise patients to store encorafenib in the original bottle with desiccant and to keep the cap of the bottle tightly closed. Do not remove the desiccants from the bottle. # Precautions with Alcohol Alcohol-Encorafenib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Braftovi # Look-Alike Drug Names There is limited information regarding Encorafenib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Braftovi
f5147187c31e5bc57b0f81c39a402e62ff203ab6	wikidoc	Brain death	Brain death # Overview Brain death is a legal definition of death that emerged in the 1960's as a response to the ability to resuscitate individuals and mechanically keep the heart and lungs working. In simple terms, brain death is the irreversible end of all brain activity. It should not be confused with a persistent vegetative state. ## Legal history of brain death Traditionally, both the legal and medical community determined death through the end of certain bodily functions, especially respiration and heartbeat. With the increasing ability of the medical community to resuscitate people with no heart beat, respiration or other visible signs of life, the need for a better definition of death became obvious. This need gained greater urgency with the widespread use of life support equipment, which can maintain body functions indefinitely, as well as rising capabilities and demand for organ transplantation. In the U.S., an ad hoc committee at Harvard Medical School published a pivotal 1968 report to define irreversible coma. The Harvard criteria gradually gained consensus toward what is now known as brain death. In the wake of the 1976 Karen Ann Quinlan controversy, state legislatures moved to accept brain death as an acceptable indication of death. Finally, a presidential commission issued a landmark 1981 report — Defining Death: Medical. Legal, and Ethical Issues in the Determination of Death. — that rejected the "higher brain" approach to death in favor of a "whole brain" definition. This report was the basis for the Uniform Definition of Death Act, which is now the law in almost all fifty states. Today, both the legal and medical communities use "brain death" as a legal definition of death. Using brain-death criteria, the medical community can declare a person legally dead even if life support equipment keeps the body's metabolic processes working. The first nation to adopt brain death as a legal definition death was Finland in 1971. In the United States, Kansas enacted a similar law earlier. ### Religion and brain death Despite the adoption of whole brain criteria in the United States and "brainstem" criteria in the United Kingdom, there has been opposition to brain death criteria from the beginning. Traditionalist Orthodox Jews have staunchly defended the traditional conception of death in the U.S. and Israel (See Time of Death by J. David Bleich.) Conversely, some modern Orthodox rabbis and Israel's Chief Rabbinate have adopted determinations of death based on brain function. (See Moshe Tendler's elucidation of Rabbi Moshe Feinstein's responsa.) As a result, Orthodox Jewish ethics has been sharply divided over key death-related policies. Tactically, Orthodox Jewish opponents to brain death have requested waivers from state law, as a matter of religious freedom, so as to continue relying on traditional indicia. Meanwhile, proponents have been active in advocating organ donations and transplants. Similarly, Islamic views on brain death are mixed. ("Views of Muslim scholars on organ donation and brain death" Transplantation Proceedings, Volume 29, Issue 8, December 1997, Page 3217. Faroque A. Khan, The Definition of Death in Islam: Can Brain Death Be Used as A Criteria of Death in Islam? Farhat Moazam, Bioethics and Organ Transplantation in a Muslim Society: A Study in Culture, Ethnography, and Religion, Indiana University Press, 2006, p.32ff.) The 1981 federal report, Defining Death, found that Catholic and Protestant theologies did not object to brain death criteria. Indeed, Dennis Horan, president of the pro-life group American Citizens United for Life, stated: Legislation limiting the concept of brain death to the irreversible cessation of total function of the brain, including the brain stem, is beneficial and does not undermine any of the values we seek to support. More recently, the findings of the 1981 President's Commission Report have been questioned (Beyond Brain Death). The new attack on brain death criteria has been multi-pronged. First, the view that brain death marks the end of the integrated unity of the human organism has been questioned. Alan Shewmon ("Chronic 'Brain Death': Meta-analysis and Conceptual Consequences") has argued that the body as a whole is the central integrator of the organism rather than the brain. He appeals to, among other reasons, brain dead pregnant women who have lived up to 200+ days and given birth to healthy children, as well as to a brain dead boy who lived over fourteen years on a ventilator and with basic nursing support. Others, such as David Evans (in Beyond Brain Death and in Finis Vitae: Is Brain Death Still Life), have argued that there is insufficient evidence that the entire brain is dead in a brain dead individual. Some brain dead individuals have continuing EEG activity ("Brief Review: The role of ancillary tests in the neurological determination of death" by Young, Shemie, and Doig) and others maintain normal or near-normal body temperature, implying continuing hypothalamic function ("The brain and somatic integration" by Shewmon). In Catholic medical ethics, Pope Pius XII stated that death is determined by medical experts and it "does not fall within the competence of the Church." (See, "The Prolongation of Life" in The Pope Speaks 4:4 1958) Advocates of brain death criteria have claimed that this implies that the church is bound to support the view of the medical community on this issue. More recently, the Pontifical Academy of Science has upheld Catholic doctrine. ("The determination of brain death and its relationship to human death." Working Group, 10-14 December 1989, pp. xxvii-210 ) Nevertheless, there was some Catholic dissent on neurological criteria for death, e.g., see "Brain death is not death" essay. This was not without controversy, as a volume by opponents of brain death criteria who participated in a 2005 conference at the Pontifical Academy of Sciences was published in 2006 by a publisher outside the Vatican (Finis Vitae: Is Brain Death Still Life). ## Medical criteria for determining brain death A brain-dead individual has no clinical evidence of brain function upon physical examination. This includes no response to pain and no cranial nerve reflexes. Reflexes include pupillary response (fixed pupils), oculocephalic reflex, corneal reflex, no response to the caloric reflex test and no spontaneous respirations. It is important to distinguish between brain death and states that mimic brain death (e.g., barbiturate intoxication, alcohol intoxication, sedative overdose, hypothermia, hypoglycemia, coma or chronic vegetative states). Some comatose patients can recover, and some patients with severe irreversible neurologic dysfunction will nonetheless retain some lower brain functions such as spontaneous respiration, despite the losses of both cortex and brainstem functionality. Thus, anencephaly, in which there is no higher brain present, is generally not considered brain death, though it is certainly an irreversible condition in which it may be appropriate to withdraw life support. Note that brain electrical activity can stop completely, or drop to such a low level as to be undetectable with most equipment. This includes a flat EEG during deep anaesthesia or cardiac arrest. However, the EEG is not required in the United States, but is considered to have confirmatory value. The diagnosis of brain death needs to be rigorous to determine whether the condition is irreversible. Legal criteria vary, but it generally requires neurological exams by two independent physicians. The exams must show complete absence of brain function, and may include two isoelectric (flat-line) EEGs 24 hours apart. The proposed Uniform Determination Of Death Act in the United States attempts to standardize criteria. The patient should have a normal temperature and be free of drugs that can suppress brain activity if the diagnosis is to be made on EEG criteria. Alternatively, a radionuclide cerebral blood flow scan that shows complete absence of intracranial blood flow can be used to confirm the diagnosis without performing EEGs. ## Brain death and consciousness It is presumed that a permanent cessation of electrical activity indicates the end of consciousness. Those who view the neo-cortex of the brain as solely responsible for consciousness, however, argue that electrical activity there should be the only consideration when defining death. In many cases, especially when elevated intracranial pressure prevents blood flow into the brain, the entire brain is nonfunctional; however, some injuries may affect only the neo-cortex. ## Brain death and organ donation Most organ donation for organ transplantation is done in the setting of brain death. In some nations (for instance, Belgium, Brazil, Poland, Portugal and France) everyone is automatically an organ donor, although some jurisdictions (such as Singapore) allow opting out of the system. Elsewhere, consent from family members or next-of-kin is required for organ donation. The non-living donor is kept on ventilator support until the organs have been surgically removed. If a brain-dead individual is not an organ donor, ventilator and drug support is discontinued and cardiac death is allowed to occur.	Brain death # Overview Brain death is a legal definition of death that emerged in the 1960's as a response to the ability to resuscitate individuals and mechanically keep the heart and lungs working. In simple terms, brain death is the irreversible end of all brain activity. It should not be confused with a persistent vegetative state. ## Legal history of brain death Traditionally, both the legal and medical community determined death through the end of certain bodily functions, especially respiration and heartbeat. With the increasing ability of the medical community to resuscitate people with no heart beat, respiration or other visible signs of life, the need for a better definition of death became obvious. This need gained greater urgency with the widespread use of life support equipment, which can maintain body functions indefinitely, as well as rising capabilities and demand for organ transplantation. In the U.S., an ad hoc committee at Harvard Medical School published a pivotal 1968 report to define irreversible coma. The Harvard criteria gradually gained consensus toward what is now known as brain death. In the wake of the 1976 Karen Ann Quinlan controversy, state legislatures moved to accept brain death as an acceptable indication of death. Finally, a presidential commission issued a landmark 1981 report — Defining Death: Medical. Legal, and Ethical Issues in the Determination of Death. — that rejected the "higher brain" approach to death in favor of a "whole brain" definition. This report was the basis for the Uniform Definition of Death Act, which is now the law in almost all fifty states. Today, both the legal and medical communities use "brain death" as a legal definition of death. Using brain-death criteria, the medical community can declare a person legally dead even if life support equipment keeps the body's metabolic processes working. The first nation to adopt brain death as a legal definition death was Finland in 1971. In the United States, Kansas enacted a similar law earlier.[1] ### Religion and brain death Despite the adoption of whole brain criteria in the United States and "brainstem" criteria in the United Kingdom, there has been opposition to brain death criteria from the beginning. Traditionalist Orthodox Jews have staunchly defended the traditional conception of death in the U.S. and Israel (See Time of Death by J. David Bleich.) Conversely, some modern Orthodox rabbis and Israel's Chief Rabbinate have adopted determinations of death based on brain function. (See Moshe Tendler's elucidation of Rabbi Moshe Feinstein's responsa.) As a result, Orthodox Jewish ethics has been sharply divided over key death-related policies. Tactically, Orthodox Jewish opponents to brain death have requested waivers from state law, as a matter of religious freedom, so as to continue relying on traditional indicia.[2] Meanwhile, proponents have been active in advocating organ donations and transplants.[1] Similarly, Islamic views on brain death are mixed. ("Views of Muslim scholars on organ donation and brain death" Transplantation Proceedings, Volume 29, Issue 8, December 1997, Page 3217. Faroque A. Khan, The Definition of Death in Islam: Can Brain Death Be Used as A Criteria of Death in Islam? Farhat Moazam, Bioethics and Organ Transplantation in a Muslim Society: A Study in Culture, Ethnography, and Religion, Indiana University Press, 2006, p.32ff.) The 1981 federal report, Defining Death, found that Catholic and Protestant theologies did not object to brain death criteria. Indeed, Dennis Horan, president of the pro-life group American Citizens United for Life, stated: Legislation limiting the concept of brain death to the irreversible cessation of total function of the brain, including the brain stem, is beneficial and does not undermine any of the values we seek to support. More recently, the findings of the 1981 President's Commission Report have been questioned (Beyond Brain Death). The new attack on brain death criteria has been multi-pronged. First, the view that brain death marks the end of the integrated unity of the human organism has been questioned. Alan Shewmon ("Chronic 'Brain Death': Meta-analysis and Conceptual Consequences") has argued that the body as a whole is the central integrator of the organism rather than the brain. He appeals to, among other reasons, brain dead pregnant women who have lived up to 200+ days and given birth to healthy children, as well as to a brain dead boy who lived over fourteen years on a ventilator and with basic nursing support. Others, such as David Evans (in Beyond Brain Death and in Finis Vitae: Is Brain Death Still Life), have argued that there is insufficient evidence that the entire brain is dead in a brain dead individual. Some brain dead individuals have continuing EEG activity ("Brief Review: The role of ancillary tests in the neurological determination of death" by Young, Shemie, and Doig) and others maintain normal or near-normal body temperature, implying continuing hypothalamic function ("The brain and somatic integration" by Shewmon). In Catholic medical ethics, Pope Pius XII stated that death is determined by medical experts and it "does not fall within the competence of the Church." (See, "The Prolongation of Life" in The Pope Speaks 4:4 1958) Advocates of brain death criteria have claimed that this implies that the church is bound to support the view of the medical community on this issue. More recently, the Pontifical Academy of Science has upheld Catholic doctrine. ("The determination of brain death and its relationship to human death." Working Group, 10-14 December 1989, pp. xxvii-210 [2] [3]) Nevertheless, there was some Catholic dissent on neurological criteria for death, e.g., see "Brain death is not death" essay. This was not without controversy, as a volume by opponents of brain death criteria who participated in a 2005 conference at the Pontifical Academy of Sciences was published in 2006 by a publisher outside the Vatican (Finis Vitae: Is Brain Death Still Life). ## Medical criteria for determining brain death A brain-dead individual has no clinical evidence of brain function upon physical examination. This includes no response to pain and no cranial nerve reflexes. Reflexes include pupillary response (fixed pupils), oculocephalic reflex, corneal reflex, no response to the caloric reflex test and no spontaneous respirations. It is important to distinguish between brain death and states that mimic brain death (e.g., barbiturate intoxication, alcohol intoxication, sedative overdose, hypothermia, hypoglycemia, coma or chronic vegetative states). Some comatose patients can recover, and some patients with severe irreversible neurologic dysfunction will nonetheless retain some lower brain functions such as spontaneous respiration, despite the losses of both cortex and brainstem functionality. Thus, anencephaly, in which there is no higher brain present, is generally not considered brain death, though it is certainly an irreversible condition in which it may be appropriate to withdraw life support. Note that brain electrical activity can stop completely, or drop to such a low level as to be undetectable with most equipment. This includes a flat EEG during deep anaesthesia or cardiac arrest. However, the EEG is not required in the United States, but is considered to have confirmatory value. The diagnosis of brain death needs to be rigorous to determine whether the condition is irreversible. Legal criteria vary, but it generally requires neurological exams by two independent physicians. The exams must show complete absence of brain function, and may include two isoelectric (flat-line) EEGs 24 hours apart. The proposed Uniform Determination Of Death Act in the United States attempts to standardize criteria. The patient should have a normal temperature and be free of drugs that can suppress brain activity if the diagnosis is to be made on EEG criteria. Alternatively, a radionuclide cerebral blood flow scan that shows complete absence of intracranial blood flow can be used to confirm the diagnosis without performing EEGs. ## Brain death and consciousness It is presumed that a permanent cessation of electrical activity indicates the end of consciousness. Those who view the neo-cortex of the brain as solely responsible for consciousness, however, argue that electrical activity there should be the only consideration when defining death. In many cases, especially when elevated intracranial pressure prevents blood flow into the brain, the entire brain is nonfunctional; however, some injuries may affect only the neo-cortex. ## Brain death and organ donation Most organ donation for organ transplantation is done in the setting of brain death. In some nations (for instance, Belgium, Brazil, Poland, Portugal and France) everyone is automatically an organ donor, although some jurisdictions (such as Singapore) allow opting out of the system. Elsewhere, consent from family members or next-of-kin is required for organ donation. The non-living donor is kept on ventilator support until the organs have been surgically removed. If a brain-dead individual is not an organ donor, ventilator and drug support is discontinued and cardiac death is allowed to occur.	https://www.wikidoc.org/index.php/Brain-dead
d34910076d8f77fa5bfa287aa875bf897963e823	wikidoc	Brain types	Brain types # Overview Brain typing, which combines elements from neuroscience, physiology, and psychology, is a system developed by Jonathan P. Niednagel. It is based on ideas of the psychological typology of Carl Jung, and the later work by Katharine Cooks Briggs and Isabel Briggs Myers known as the Myers-Briggs Type Indicator (MBTI). What separates brain types from Jungian typology, and its offshoots such as the MBTI and Socionics, is its emphasis on mental and motor skills. Each of the sixteen brain types is said to specialize in certain regions of the brain responsible for varying degrees of mental and motor skills. Niednagel believes types are inherited, possessing a genetic basis. Niednagel started to develop brain typing in the 1970s while coaching little league baseball. He observed that children with similar personalities also had similar motor skills. Having spent several decades on research, Niednagel's work began to receive more attention in the 1990s, particularly in the arena of professional sports. Perhaps the most well-known event related to brain typing was Niednagel's prediction in 1998 that Peyton Manning would become a star quarterback in the National Football League (NFL), and that the similarly hyped Ryan Leaf would perform poorly in the league. His prediction came true as Peyton Manning has become one of football's best quarterbacks while Ryan Leaf is remembered as one of the worst busts in football draft history. With all the effort and research that Niednagel has put into brain types, it has not yet been validated through science. It is also uncertain how much application brain types has beyond the realm of sports, since the primary difference between brain typing and related typologies is the motor skill emphasis. # Brain Types and Motor Skills Niednagel divides the types into four basic motor skill groupings: SF, ST, NF, and NT. SF, or 'Sensing-Feeling' types (ESFJ, ESFP, ISFJ, ISFP), are said to excel in the region of the brain responsible for gross motor skills. ST, or 'Sensing-Thinking' types (ESTJ, ESTP, ISTJ, ISTP), are thought to possess the best fine motor skills of the four groups. NF, or 'Intuitive-Feeling' types (ENFJ, ENFP, INFJ, INFP), excel in the auditory cortex, which is responsible for various hearing and language skills. NT, or 'Intuitive-Thinking' types (ENTJ, ENTP, INTJ, INTP), are believed to excel in the cerebral cortex, where abstract levels of reasoning occur. # Brain Types and Mental Skills The types can also be broken down by letter, which denote certain mental skills: Extroverted (E): -Located in frontal (anterior) lobes of brain -More energy-expending as opposed to energy-conserving Introverted (I): -Located in rear (posterior) lobes of brain -More energy-conserving as opposed to energy-expending Sensing (S): -Brain more focused on physical-concrete functions than abstractions Intuition (N): -Brain more focused on abstract-mental functions than the physical and concrete world Thinking (T): -Brain more objectively focused, preferring the inanimate world (objects, things, systems, etc.) Feeling (F): -Brain more subjectively focused, preferring the animate world (life, people, relationships, etc.) Judging (J): -Left-brain dominant; inclined toward linear mental functioning; more analytic mental process -Motor skill patterns are more rigid than fluid (tend to be less physically coordinated) Perceiving (P): -Right-brain dominant; inclined toward spatial mental functioning; more synthetic mental process -Motor skill patterns are more fluid than rigid (tend to be more physically coordinated) # Commercialization and criticism Educational society and members of American Psychological Association criticize brain types as not valid and built for commercial purposes only. Mr. Niednagel, who has no scientific degree in psychological or medical fields, only a Bachelor’s degree in Business Finance from California State University, Long Beach., claims his methods as being the only valid ones. Another post boasts of a 100% accuracy rate in assessing and localizing brain functioning on the basis of "eyeballing" and then analyzing body language, posture, motor activity, and speech. California Neuroscience Researchers and Professors requested that Niednagel remove their "endorsements" once they inspected the Brain Type website and discovered that they were being used to bolster Niednagel's stature. Dr. Sandbek, in his publication Brain Typing: The Pseudoscience of Cold Reading criticized validity of brain types and claimed "how closely the Brain Typing of Jonathan P. Niednagel fits as a pseudoscience".	Brain types # Overview Brain typing, which combines elements from neuroscience, physiology, and psychology, is a system developed by Jonathan P. Niednagel. It is based on ideas of the psychological typology of Carl Jung, and the later work by Katharine Cooks Briggs and Isabel Briggs Myers known as the Myers-Briggs Type Indicator (MBTI). What separates brain types from Jungian typology, and its offshoots such as the MBTI and Socionics, is its emphasis on mental and motor skills. Each of the sixteen brain types is said to specialize in certain regions of the brain responsible for varying degrees of mental and motor skills. Niednagel believes types are inherited, possessing a genetic basis. Niednagel started to develop brain typing in the 1970s while coaching little league baseball. He observed that children with similar personalities also had similar motor skills. Having spent several decades on research, Niednagel's work began to receive more attention in the 1990s, particularly in the arena of professional sports. Perhaps the most well-known event related to brain typing was Niednagel's prediction in 1998 that Peyton Manning would become a star quarterback in the National Football League (NFL), and that the similarly hyped Ryan Leaf would perform poorly in the league. His prediction came true as Peyton Manning has become one of football's best quarterbacks while Ryan Leaf is remembered as one of the worst busts in football draft history. With all the effort and research that Niednagel has put into brain types, it has not yet been validated through science. It is also uncertain how much application brain types has beyond the realm of sports, since the primary difference between brain typing and related typologies is the motor skill emphasis. # Brain Types and Motor Skills Niednagel divides the types into four basic motor skill groupings: SF, ST, NF, and NT. SF, or 'Sensing-Feeling' types (ESFJ, ESFP, ISFJ, ISFP), are said to excel in the region of the brain responsible for gross motor skills. ST, or 'Sensing-Thinking' types (ESTJ, ESTP, ISTJ, ISTP), are thought to possess the best fine motor skills of the four groups. NF, or 'Intuitive-Feeling' types (ENFJ, ENFP, INFJ, INFP), excel in the auditory cortex, which is responsible for various hearing and language skills. NT, or 'Intuitive-Thinking' types (ENTJ, ENTP, INTJ, INTP), are believed to excel in the cerebral cortex, where abstract levels of reasoning occur. # Brain Types and Mental Skills The types can also be broken down by letter, which denote certain mental skills: Extroverted (E): -Located in frontal (anterior) lobes of brain -More energy-expending as opposed to energy-conserving Introverted (I): -Located in rear (posterior) lobes of brain -More energy-conserving as opposed to energy-expending Sensing (S): -Brain more focused on physical-concrete functions than abstractions Intuition (N): -Brain more focused on abstract-mental functions than the physical and concrete world Thinking (T): -Brain more objectively focused, preferring the inanimate world (objects, things, systems, etc.) Feeling (F): -Brain more subjectively focused, preferring the animate world (life, people, relationships, etc.) Judging (J): -Left-brain dominant; inclined toward linear mental functioning; more analytic mental process -Motor skill patterns are more rigid than fluid (tend to be less physically coordinated) Perceiving (P): -Right-brain dominant; inclined toward spatial mental functioning; more synthetic mental process -Motor skill patterns are more fluid than rigid (tend to be more physically coordinated) # Commercialization and criticism Educational society and members of American Psychological Association criticize brain types as not valid and built for commercial purposes only[1]. Mr. Niednagel, who has no scientific degree in psychological or medical fields, only a Bachelor’s degree in Business Finance from California State University, Long Beach., claims his methods as being the only valid ones. Another post boasts of a 100% accuracy rate in assessing and localizing brain functioning on the basis of "eyeballing" and then analyzing body language, posture, motor activity, and speech. California Neuroscience Researchers and Professors requested that Niednagel remove their "endorsements" once they inspected the Brain Type website and discovered that they were being used to bolster Niednagel's stature[1]. Dr. Sandbek, in his publication Brain Typing: The Pseudoscience of Cold Reading criticized validity of brain types and claimed "how closely the Brain Typing of Jonathan P. Niednagel fits as a pseudoscience"[2].	https://www.wikidoc.org/index.php/Brain_types
00d58233ac7edbd460c458897dd0fc4654af1f70	wikidoc	Breast cyst	Breast cyst # Overview A breast cyst appears as a lump on the breast, which may appear to be similar to breast cancer but is generally benign. While cancer is the overgrowth of cells, a cyst is a closed sac having a distinct membrane and develosion on the nearby tissue. # Diagnosis A preliminary test for the presence of a breast cyst is an ultrasound examination, which may determine whether the lump is malignant, i.e. cancerous. # Treatment Typical treatment involves a Needle aspiration biopsy, or an incision and removal.	Breast cyst # Overview A breast cyst appears as a lump on the breast, which may appear to be similar to breast cancer but is generally benign. While cancer is the overgrowth of cells, a cyst is a closed sac having a distinct membrane and develosion on the nearby tissue. # Diagnosis A preliminary test for the presence of a breast cyst is an ultrasound examination, which may determine whether the lump is malignant, i.e. cancerous. # Treatment Typical treatment involves a Needle aspiration biopsy, or an incision and removal. # External links - BreastCancer.org article - WDXCyber - Informative article Template:WS	https://www.wikidoc.org/index.php/Breast_cyst
013bd467f9c2fdc78b3ade74f9a2169ba7365c86	wikidoc	Breast milk	Breast milk # Overview Breast milk usually refers to the milk produced by a human female which is usually fed to infants by breastfeeding. It provides the primary source of nutrition for newborns before they are able to eat solid food and digest a wider variety of food. # Production Under the influence of the hormones prolactin and oxytocin, women produce milk after pregnancy to feed their baby. The initial milk produced is often referred to as colostrum, which is high in the immunoglobulin IgA, which coats the gastrointestinal tract. This helps to protect the newborn until its own immune system is functioning properly along with creating a mild laxative effect, expelling meconium and helping to prevent the build up of bilirubin (a contributory factor in jaundice). There are many reasons a mother may not produce enough breast milk. Some of the most common are: improper latch, not nursing or pumping enough to meet supply, certain medications, birth control, illness, dehydration, or (not commonly) a physical inability to produce. Lack of supply can be addressed by nursing or/and pumping more frequently. The more the mother nurses her baby, or pumps, the more milk is produced. It is very helpful to nurse on demand - to nurse when the baby wants to nurse rather than on a schedule. If pumping it is helpful to have an electric high grade pump so that all of the milk ducts are stimulated. Some mothers try to increase their milk supply in other ways - by taking the herb fenugreek, used for hundreds of years to increase supply ("Mother's Milk" teas contain fenugreek as well as other supply-increasing herbs); there are also prescription medications that can be used, such as Domperidone (off-label use) and Reglan. Oatmeal or Coconut have also been known to increase milk production in lactating women. # Composition The exact integrated properties of breast milk are not entirely understood, but the nutrient content after this period is relatively consistent and draws its ingredients from the mother's food supply. If that supply is found lacking, content is obtained from the mother's bodily stores. The exact composition of breast milk varies from day to day, depending on food consumption and environment, meaning that the ratio of water to fat fluctuates. Foremilk, the milk released at the beginning of a feed, is watery, low in fat and high in carbohydrates relative to the creamier hindmilk which is released as the feed progresses. The breast can never be truly "emptied" since milk production is a continuous biological process. Human milk contains 0.8% to 0.9% protein, 3% to 5% fat, 6.9% to 7.2% carbohydrates and 0.2% ash (minerals). Carbohydrates are mainly lactose; several lactose-based oligosaccharides have been identified as minor components. The principal proteins are casein homologous to bovine beta-casein, alpha-lactalbumin, lactoferrin, IgA, lysozyme and serum albumin. Non-protein nitrogen-containing compounds, making up 25% of the milk's nitrogen, include urea, uric acid, creatine, creatinine, amino acids and nucleotides. Mother's milk has been shown to supply the a type of endocannabinoid (the natural neurotransmitters which marijuana simulates), 2-Arachidonoyl glycerol. Though now it is almost universally prescribed, in the 1950s the practice of breastfeeding went through a period where it was out of vogue and the use of infant formula was considered superior to breast milk. However, today it is now recognized that there is no commercial formula that can equal breast milk. In addition to the appropriate amounts of carbohydrate, protein and fat, breast milk also provides vitamins, minerals, digestive enzymes and hormones - all of the things that a growing infant will require. Breast milk also contains antibodies from the mother that may help the baby to resist infections. Women who are breastfeeding should consult with their physician regarding things that can be unwittingly passed to the infant via breast milk, such as alcohol, viruses (HIV or HTLV-1) or medications. Most women who do not breastfeed use infant formula, but breast milk donated by volunteers to human milk banks can be obtained by prescription. Cow's milk is recommended as a substitute, but only for children over one year old. # Comparison to other milks All mammal species produce milk, but the composition of milk for each species varies widely and other kinds of milk are often very different from human breast milk. As a rule, the milk of mammals that nurse frequently (including human babies) is less rich, or more watery, than the milk of mammals whose young nurse less often. Whole cow's milk does not contain sufficient vitamin E, iron, or essential fatty acids, which can make infants fed on cow's milk anemic. Whole cow's milk also contains excessive amounts of protein, sodium, and potassium which may put a strain on an infant's immature kidneys. In addition, the proteins and fats in whole cow's milk are more difficult for an infant to digest and absorb than the ones in breast milk. Evaporated milk may be easier to digest due to the processing of the protein but is still nutritionally inadequate. A significant minority of infants are allergic to one or more of the constituents of cow's milk. These problems can also affect formula milk derived from cow's milk.Template:Vague Goat's milk does not contain agglutinin, which means that the fat globules in goat's milk do not cluster together like they do in cow's milk, which makes goat's milk easier for an infant to digest. Goat's milk also does not contain many of the allergens found in cow's milk. However, like cow's milk, goat's milk is also unsuitable for infants as it also does not have appropriate concentrations of electrolytes and can cause intestinal irritation and anemia. Human milk is similar in flavor and texture to cow milk, but noticeably thinner and sweeter. Left in a cup, the cream will rise and form a thin layer.	Breast milk Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2] # Overview Breast milk usually refers to the milk produced by a human female which is usually fed to infants by breastfeeding. It provides the primary source of nutrition for newborns before they are able to eat solid food and digest a wider variety of food. # Production Under the influence of the hormones prolactin and oxytocin, women produce milk after pregnancy to feed their baby. The initial milk produced is often referred to as colostrum, which is high in the immunoglobulin IgA, which coats the gastrointestinal tract. This helps to protect the newborn until its own immune system is functioning properly along with creating a mild laxative effect, expelling meconium and helping to prevent the build up of bilirubin (a contributory factor in jaundice). There are many reasons a mother may not produce enough breast milk. Some of the most common are: improper latch, not nursing or pumping enough to meet supply, certain medications, birth control, illness, dehydration, or (not commonly) a physical inability to produce. Lack of supply can be addressed by nursing or/and pumping more frequently. The more the mother nurses her baby, or pumps, the more milk is produced. It is very helpful to nurse on demand - to nurse when the baby wants to nurse rather than on a schedule. If pumping it is helpful to have an electric high grade pump so that all of the milk ducts are stimulated. Some mothers try to increase their milk supply in other ways - by taking the herb fenugreek, used for hundreds of years to increase supply ("Mother's Milk" teas contain fenugreek as well as other supply-increasing herbs); there are also prescription medications that can be used, such as Domperidone (off-label use) and Reglan. Oatmeal or Coconut have also been known to increase milk production in lactating women.[citation needed] # Composition The exact integrated properties of breast milk are not entirely understood, but the nutrient content after this period is relatively consistent and draws its ingredients from the mother's food supply. If that supply is found lacking, content is obtained from the mother's bodily stores. The exact composition of breast milk varies from day to day, depending on food consumption and environment, meaning that the ratio of water to fat fluctuates. Foremilk, the milk released at the beginning of a feed, is watery, low in fat and high in carbohydrates relative to the creamier hindmilk which is released as the feed progresses. The breast can never be truly "emptied" since milk production is a continuous biological process. Human milk contains 0.8% to 0.9% protein, 3% to 5% fat, 6.9% to 7.2% carbohydrates and 0.2% ash (minerals). Carbohydrates are mainly lactose; several lactose-based oligosaccharides have been identified as minor components. The principal proteins are casein homologous to bovine beta-casein, alpha-lactalbumin, lactoferrin, IgA, lysozyme and serum albumin. Non-protein nitrogen-containing compounds, making up 25% of the milk's nitrogen, include urea, uric acid, creatine, creatinine, amino acids and nucleotides.[1][2] Mother's milk has been shown to supply the a type of endocannabinoid (the natural neurotransmitters which marijuana simulates), 2-Arachidonoyl glycerol.[3] Though now it is almost universally prescribed, in the 1950s the practice of breastfeeding went through a period where it was out of vogue and the use of infant formula was considered superior to breast milk. However, today it is now recognized that there is no commercial formula that can equal breast milk. In addition to the appropriate amounts of carbohydrate, protein and fat, breast milk also provides vitamins, minerals, digestive enzymes and hormones - all of the things that a growing infant will require. Breast milk also contains antibodies from the mother that may help the baby to resist infections. Women who are breastfeeding should consult with their physician regarding things that can be unwittingly passed to the infant via breast milk, such as alcohol, viruses (HIV or HTLV-1) or medications. Most women who do not breastfeed use infant formula, but breast milk donated by volunteers to human milk banks can be obtained by prescription.[3] Cow's milk is recommended as a substitute, but only for children over one year old. # Comparison to other milks All mammal species produce milk, but the composition of milk for each species varies widely and other kinds of milk are often very different from human breast milk. As a rule, the milk of mammals that nurse frequently (including human babies) is less rich, or more watery, than the milk of mammals whose young nurse less often. Whole cow's milk does not contain sufficient vitamin E, iron, or essential fatty acids, which can make infants fed on cow's milk anemic. Whole cow's milk also contains excessive amounts of protein, sodium, and potassium which may put a strain on an infant's immature kidneys. In addition, the proteins and fats in whole cow's milk are more difficult for an infant to digest and absorb than the ones in breast milk.[4] Evaporated milk may be easier to digest due to the processing of the protein but is still nutritionally inadequate. A significant minority of infants are allergic to one or more of the constituents of cow's milk. These problems can also affect formula milk derived from cow's milk.Template:Vague Goat's milk does not contain agglutinin, which means that the fat globules in goat's milk do not cluster together like they do in cow's milk, which makes goat's milk easier for an infant to digest. Goat's milk also does not contain many of the allergens found in cow's milk. However, like cow's milk, goat's milk is also unsuitable for infants as it also does not have appropriate concentrations of electrolytes and can cause intestinal irritation and anemia. Human milk is similar in flavor and texture to cow milk, but noticeably thinner and sweeter. Left in a cup, the cream will rise and form a thin layer.	https://www.wikidoc.org/index.php/Breast_milk
f9bb8c033478ab43870c2146446192dcba96af7c	wikidoc	Breast pump	Breast pump # Overview A breast pump is a mechanical device (powered manually or by electricity) that extracts milk from the breasts of a woman who is lactating. The breast pump was invented and patented by Edward Lasker. Mechanically, a breast pump is directly analogous to a milking machine used in commercial dairy production. A misconception is that the breast pump suctions milk out of the breast. A breast pump's job is to trigger the milk-ejection response or let-down. Most pumps achieve this goal by using suction to pull the nipple into the tunnel of the breast shield or flange then release, which counts as one cycle. Thirty to sixty cycles per minute can be expected with better quality electric breast pumps. It is important to note that in most cases the breast pump is not as efficient at removing milk from the breast as the nursing baby. The expressed breast milk (EBM) may be stored and later fed to a baby by bottle. Expressed milk may be kept at room temperature for up to ten hours (at 66-72 degrees Fahrenheit, around 20 degrees Celsius), refrigerated for up to 8 days, or frozen for six months in a deep freeze separate from a refrigerator maintained at a temperature of 0 degrees Fahrenheit or −18 degrees Celsius. Expressed milk may be donated to milk banks, which provide human breast milk to premature infants and other high-risk children whose mothers cannot provide for them. Women use breast pumps for many reasons. Many women use breast pumps to continue breastfeeding after they return to work. They use the pump to express breast milk which is later bottle fed to their child by a caregiver. A breast pump may also be used to stimulate lactation for women with a low milk supply, or who have not just given birth. A breast pump may be used to relieve engorgement, a painful condition whereby the breasts are overfull, possibly preventing a proper latch by the infant. If an infant does not latch properly for direct breastfeeding, and the mother still desires the benefits of breast milk, she may choose to pump exclusively. If the mother needs to take medication that affects the breast milk and may be harmful to the infant, the mother may "pump and dump" the breast milk to keep up her milk supply during the time period that she is on the medication and may resume nursing after the course of medication is completed. Finally, pumping may be desirable to continue lactation and its associated hormonal benefits to aid in recovery from pregnancy even if the pumped milk is not used. # Types of Breast Pumps Manual breast pumps are operated by squeezing a handle in a repetitive fashion, allowing the user to directly control the pressure and frequency of pumps. Though manual pumps are small and inexpensive, they can require significant effort and can be tiring because the user provides all the power. This style is recommended for infrequent usage such as when a woman is away from her baby for a single feeding. It is recommended that "bicycle horn" style manual pumps not be used. Though cheap, they can damage breast tissue and harbor bacteria in the rubber suction bulb, which is difficult to clean. Personal electric pumps are powered by a small motor which supplies suction through plastic tubing to a breast shield (or flange) that fits over the nipple. The portions of the pump that come into direct contact with the expressed milk must be sterilized to prevent contamination. This style provides a lot more suction, making pumping significantly faster, and allows pumping of both breasts at the same time. Electric breast pumps are ideal for when a mother will be pumping daily or more than once daily. Electric breast pumps are larger than manual ones, but portable models are available (e.g. in a backpack or shoulder bag) that allow the mother to transport the pump. Personal electric breast pumps may have different power supplies including: - AC Adapter - Batteries - Portable charging adapters - Rechargeable pumps Hospital-grade electric pumps have larger motors which provide more suction. They are relatively silent and provide more efficient, quicker expression of breast milk. Hospital-grade breast pumps are FDA-approved for multiple users as long as the collection system is changed between users. They are often used at hospitals for milk donations or for mothers who have trouble breast feeding (due to trouble latching or painful engorgement). Hospital-grade electric pumps are generally rented for personal use due to the high cost, however, they may be a good purchase option for mothers who can afford them and either have a need for them or prefer them for the convenience and speed of milk expression. Hands-free electric pumps have been on the market for several years in the form of a fitted undergarment with breast pump attachments on the areolae to allow for hands-free breastmilk pumping. Recently, new models have become available that have a self-contained collection system with no tubing or visible containers. They use ergonomic designs to cup the breast under the garments and collect breast milk while the mother goes about her daily activities. # Open Collection Systems vs. Closed Collection Systems The plastic tubing and breast shield (or flange) of an electric breast pump are commonly referred to as the collection system. When this style of breast pump was originally developed, the pump’s suction was supplied through the collection system tubing. This type of collection system design is now referred to as an open system. Today most electric breast pumps feature a closed collection system. A closed collection system has a barrier or diaphragm that separates the pump tubing from the breast shield. In this design, the suction of the pump motor lifts the diaphragm to create a vacuum within the collection system to extract milk. When an open collection system is used, the pump’s suction can cause milk to overflow into the collection system tubing, which may lead to milk particles being drawn into the pump motor. If milk leaks into the pump’s tubing, the tubes should be washed, sterilized and air-dried prior to using the pump again. Failure to thoroughly clean collection tubing may lead to mold growth within the tubing. The diaphragm in a closed system eliminates the possibility of milk being able to overflow into the pump tubing. Because milk is unable to be exposed to the pump motor, closed collection systems are considered more hygienic than open collection systems. The barrier in a closed collection system breast pump also prevents outside air from contaminating the expressed breast milk in the collection bottle, which preserves the milk’s purity. # Breast Milk Storage, Thawing, and Warming Some breast pumps are designed to be part of a "feeding system" so that the milk storage portion of the pump is the baby bottle used to feed the infant. Additionally, expressed milk may be collected in bags that are designed for freezing and storage. The following table serves as a general guideline for storage of breast milk: Directions for Thawing Frozen breast milk should be thawed in the refrigerator for 12-24 hours. For expedited thawing, keep the storage container under cool running water. Directions for Warming It is recommended to warm milk by placing in a bowl of warm water, or using a bottle warmer. It is NOT recommended to microwave breast milk or heat it on the stove top. Re-freezing It is not safe to re-freeze thawed breast milk which was previously frozen or refrigerated. If the baby does not finish the milk in one feeding, it is recommended to refrigerate and attempt another feed within 2 hours. It is very important to refrigerate the remaining breast milk between feeds if it is intended to be fed to the baby at a later time. # Insurance coverage in the United States In 2010, the Affordable Care Act (ACA), also known as "Obamacare" was passed. The ACA requires insurers to cover breast pumps and lactation support. Insurers usually require a mother to go through a durable medical equipment supplier in their network. Mothers interested in getting access to lactation support, counseling and getting a free breast pump must contact their health insurance provider and request a list of in-network durable medical equipment supplier. Some of the most well known suppliers include: - Aeroflow Breastpumps - McKesson - Byram Healthcare - Edgepark - Acelleron - Pumping Essentials - Yummy Mummy - Better Living Now - MedSource - A Breast Pump and More - A Med Supplies - Mommy Express - 1 Natural Way # Related Pages - Breastfeeding - Breast milk - Lactation	Breast pump Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2] # Overview A breast pump is a mechanical device (powered manually or by electricity) that extracts milk from the breasts of a woman who is lactating. The breast pump was invented and patented by Edward Lasker. Mechanically, a breast pump is directly analogous to a milking machine used in commercial dairy production. A misconception is that the breast pump suctions milk out of the breast. A breast pump's job is to trigger the milk-ejection response or let-down. Most pumps achieve this goal by using suction to pull the nipple into the tunnel of the breast shield or flange then release, which counts as one cycle. Thirty to sixty cycles per minute can be expected with better quality electric breast pumps. It is important to note that in most cases the breast pump is not as efficient at removing milk from the breast as the nursing baby. The expressed breast milk (EBM) may be stored and later fed to a baby by bottle. Expressed milk may be kept at room temperature for up to ten hours (at 66-72 degrees Fahrenheit, around 20 degrees Celsius), refrigerated for up to 8 days, or frozen for six months in a deep freeze separate from a refrigerator maintained at a temperature of 0 degrees Fahrenheit or −18 degrees Celsius. Expressed milk may be donated to milk banks, which provide human breast milk to premature infants and other high-risk children whose mothers cannot provide for them. Women use breast pumps for many reasons. Many women use breast pumps to continue breastfeeding after they return to work. They use the pump to express breast milk which is later bottle fed to their child by a caregiver. A breast pump may also be used to stimulate lactation for women with a low milk supply, or who have not just given birth. A breast pump may be used to relieve engorgement, a painful condition whereby the breasts are overfull, possibly preventing a proper latch by the infant. If an infant does not latch properly for direct breastfeeding, and the mother still desires the benefits of breast milk, she may choose to pump exclusively. If the mother needs to take medication that affects the breast milk and may be harmful to the infant, the mother may "pump and dump" the breast milk to keep up her milk supply during the time period that she is on the medication and may resume nursing after the course of medication is completed. Finally, pumping may be desirable to continue lactation and its associated hormonal benefits to aid in recovery from pregnancy even if the pumped milk is not used. [1] # Types of Breast Pumps Manual breast pumps are operated by squeezing a handle in a repetitive fashion, allowing the user to directly control the pressure and frequency of pumps. Though manual pumps are small and inexpensive, they can require significant effort and can be tiring because the user provides all the power. This style is recommended for infrequent usage such as when a woman is away from her baby for a single feeding. It is recommended that "bicycle horn" style manual pumps not be used. Though cheap, they can damage breast tissue and harbor bacteria in the rubber suction bulb, which is difficult to clean.[2] Personal electric pumps are powered by a small motor which supplies suction through plastic tubing to a breast shield (or flange) that fits over the nipple. The portions of the pump that come into direct contact with the expressed milk must be sterilized to prevent contamination. This style provides a lot more suction, making pumping significantly faster, and allows pumping of both breasts at the same time. Electric breast pumps are ideal for when a mother will be pumping daily or more than once daily. Electric breast pumps are larger than manual ones, but portable models are available (e.g. in a backpack or shoulder bag) that allow the mother to transport the pump. Personal electric breast pumps may have different power supplies including: - AC Adapter - Batteries - Portable charging adapters - Rechargeable pumps Hospital-grade electric pumps have larger motors which provide more suction. They are relatively silent and provide more efficient, quicker expression of breast milk. Hospital-grade breast pumps are FDA-approved for multiple users as long as the collection system is changed between users. They are often used at hospitals for milk donations or for mothers who have trouble breast feeding (due to trouble latching or painful engorgement). Hospital-grade electric pumps are generally rented for personal use due to the high cost, however, they may be a good purchase option for mothers who can afford them and either have a need for them or prefer them for the convenience and speed of milk expression. Hands-free electric pumps have been on the market for several years in the form of a fitted undergarment with breast pump attachments on the areolae to allow for hands-free breastmilk pumping. Recently, new models have become available that have a self-contained collection system with no tubing or visible containers. They use ergonomic designs to cup the breast under the garments and collect breast milk while the mother goes about her daily activities. # Open Collection Systems vs. Closed Collection Systems The plastic tubing and breast shield (or flange) of an electric breast pump are commonly referred to as the collection system. When this style of breast pump was originally developed, the pump’s suction was supplied through the collection system tubing. This type of collection system design is now referred to as an open system. Today most electric breast pumps feature a closed collection system. A closed collection system has a barrier or diaphragm that separates the pump tubing from the breast shield. In this design, the suction of the pump motor lifts the diaphragm to create a vacuum within the collection system to extract milk. When an open collection system is used, the pump’s suction can cause milk to overflow into the collection system tubing, which may lead to milk particles being drawn into the pump motor. If milk leaks into the pump’s tubing, the tubes should be washed, sterilized and air-dried prior to using the pump again. Failure to thoroughly clean collection tubing may lead to mold growth within the tubing. The diaphragm in a closed system eliminates the possibility of milk being able to overflow into the pump tubing. Because milk is unable to be exposed to the pump motor, closed collection systems are considered more hygienic than open collection systems. The barrier in a closed collection system breast pump also prevents outside air from contaminating the expressed breast milk in the collection bottle, which preserves the milk’s purity. # Breast Milk Storage, Thawing, and Warming Some breast pumps are designed to be part of a "feeding system" so that the milk storage portion of the pump is the baby bottle used to feed the infant. Additionally, expressed milk may be collected in bags that are designed for freezing and storage. The following table serves as a general guideline for storage of breast milk:[3][4][5][6][7][8][9] Directions for Thawing Frozen breast milk should be thawed in the refrigerator for 12-24 hours. For expedited thawing, keep the storage container under cool running water. Directions for Warming It is recommended to warm milk by placing in a bowl of warm water, or using a bottle warmer. It is NOT recommended to microwave breast milk or heat it on the stove top. Re-freezing It is not safe to re-freeze thawed breast milk which was previously frozen or refrigerated. If the baby does not finish the milk in one feeding, it is recommended to refrigerate and attempt another feed within 2 hours. It is very important to refrigerate the remaining breast milk between feeds if it is intended to be fed to the baby at a later time. # Insurance coverage in the United States In 2010, the Affordable Care Act (ACA), also known as "Obamacare" was passed. The ACA requires insurers to cover breast pumps and lactation support.[10] Insurers usually require a mother to go through a durable medical equipment supplier in their network. Mothers interested in getting access to lactation support, counseling and getting a free breast pump must contact their health insurance provider and request a list of in-network durable medical equipment supplier.[11] Some of the most well known suppliers include: - Aeroflow Breastpumps - McKesson - Byram Healthcare - Edgepark - Acelleron - Pumping Essentials - Yummy Mummy - Better Living Now - MedSource - A Breast Pump and More - A Med Supplies - Mommy Express - 1 Natural Way # Related Pages - Breastfeeding - Breast milk - Lactation	https://www.wikidoc.org/index.php/Breast_pump
9163d6288ab875e4061cfc6522726d5d7c1bcbe9	wikidoc	Brett's law	Brett's law Brett's law is a name commonly given to a Delaware statute (SB259) generally prohibiting use of the psychoactive herb Salvia divinorum. A few other American States have proposed or introduced similar laws. The law was named after Brett Chidester (1988 - 23 January, 2006), an American teenage suicide. The law was sponsored by Delaware state senator Senator Karen E. Peterson, and signed into law three months after the teen's death. It classifies Salvia divinorum as a Delaware Schedule I controlled substance, analogous to Federal Schedule I. Chidester’s parents have argued that the herb played a major role in the teenager's death, and campaigned for Schedule-I-like legislation beyond their home state of Delaware. # Brett Chidester case ## Possible contributory factors Suicide is currently the third leading cause of death amongst 15-24 year olds in the US. The suicide rate for white males aged 15-24 has tripled since 1950 (source: National Center for Health Statistics, American Foundation for Suicide Prevention). Contributory factors underlying any individual suicide may be complex and not simply reducible to a single cause. With this in mind, it is worth considering further lifestyle and behavioural aspects along with any relevant research findings which may have a bearing. Although Salvia divinorum, alcohol, and other contributing factors have been implicated in Chidester's suicide, no concrete conclusion has been reached. His death certificate was altered to add Salvia divinorum as a contributing factor, but no explanation was given for this (see below). In addition, according to some news stories, his mother Kathy Chidester does not blame Salvia divinorum exclusively for Chidester's death, but rather lists it as an unfortunate factor to an already deadly mix of causes. ### Salvia divinorum Over three months after Chidester's suicide, with no evidence of any trace of salvinorin being found in his system, Delaware’s deputy chief medical examiner, Dr. Adrienne Sekula-Perlman, altered his death certificate to include Salvia divinorum use as a contributing cause of his death. She has subsequently refused to comment on her decision. It is difficult to determine how much Salvia divinorum really contributed to the death of Chidester and the association with his suicide has been widely debated. Contrary to some news reports, his suicide note did not mention Salvia. Chidester had written about his experiences, and some published accounts have invited the inference they were written just prior to his death. His diary or journal entries said: Further context is lacking however as his journals have not been fully published. While it has been alleged that the use of Salvia divinorum may have triggered in Chidester a depressional reaction leading to suicide, anectodal information suggests that Salvia divinorum acts instead as an anti-depressant. Furthermore, Salvia divinorum is considered relatively non-toxic (no lethal doses are known), non-addictive, short-acting (its effects lasting few minutes), with no significant deleterious long-term side-effects. There have been no other reported cases of Salvia divinorum related suicides (or accidental deaths) anywhere else in the world. It may be argued that this simply reflects Salvia’s relative obscurity, however, a simple Google search of 'Salvia divinorum' returns ~1,500,000 results which is suggestive of Salvia’s fairly significant profile and repute. Due to the short acting effect of Salvia divinorum, lasting only few minutes, it is unlikely that Chidester was under the direct influence of the drug when he committed suicide. His parents knew he had experimented with Salvia divinorum and asked him to stop. He said he would discontinue using it, so it is uncertain if he was still taking the herb before his death. Reports have not suggested in what form Chidester took the herb. A concentrated preparation of the leaf called Salvia extract, with relative strength suggested by terms such as 5x, 10x, 20x, even 30x, can be smoked in place of untreated leaves. It has yet to be established whether he was using natural leaf or a higher potency extract (and, if an extract, at what strength), or indeed if he was using any other form such as Salvia tincture. ### Alcohol The extent and significance of Chidester’s use of alcohol is a matter of contention. Groups concerned with such issues report that the suicide rate for teenage drinkers is nearly twice as high as that for non-drinkers. Alcohol Concern’s suicide briefing details many points regarding the link between alcohol use and suicide, including: - Alcohol may be a factor in as many as 65% of suicide attempts (DoH 1993) - An international comparison found a clear association between alcohol consumption and suicide in 9 out of 13 countries studied (Lester 1995) - Alcohol misuse may lead to loss of self-esteem and hence to depression. These psychological changes may predispose someone to suicide (Kendall 1983) On April 20th 2006 Mothers Against Drunk Driving and Nationwide Mutual Insurance Company announced Gallup survey results on underage drinking. The results highlight a major public misperception regarding the severity of teen alcohol use. MADD's national president, Glynn R. Birch, said Chidester's death was reported locally by Delaware Online and subsequently by a number of media outlets including CNN (links below), NBC , ABC , USAToday , W*USA 9 , KATV(Channel7) and KXAN . None of these or any other media stories on the issue have mentioned his alcohol use, all instead focusing on Salvia divinorum. ### Other risk factors Chidester was suffering from acne which has a general association with depression and thoughts of suicide . To treat his acne, he was also taking minocycline which can have side effects that may impair thinking or reactions . His parents divorced when he was three. A study from the Research Data Centre program published in the Journal of Marriage and Family found that children whose parents divorce show higher levels of depression, as well as higher levels of anti-social behaviour, than children whose parents remain married. The parents have conceded that he may have been suffering from general depression.	Brett's law Brett's law is a name commonly given to a Delaware statute (SB259) generally prohibiting use of the psychoactive herb Salvia divinorum. A few other American States have proposed or introduced similar laws. The law was named after Brett Chidester (1988 - 23 January, 2006), an American teenage suicide. The law was sponsored by Delaware state senator Senator Karen E. Peterson, and signed into law three months after the teen's death. It classifies Salvia divinorum as a Delaware Schedule I controlled substance, analogous to Federal Schedule I. Chidester’s parents have argued that the herb played a major role in the teenager's death, and campaigned for Schedule-I-like legislation beyond their home state of Delaware. [1] # Brett Chidester case ## Possible contributory factors Suicide is currently the third leading cause of death amongst 15-24 year olds in the US. The suicide rate for white males aged 15-24 has tripled since 1950 (source: National Center for Health Statistics, American Foundation for Suicide Prevention). Contributory factors underlying any individual suicide may be complex and not simply reducible to a single cause. With this in mind, it is worth considering further lifestyle and behavioural aspects along with any relevant research findings which may have a bearing. Although Salvia divinorum, alcohol, and other contributing factors have been implicated in Chidester's suicide, no concrete conclusion has been reached. His death certificate was altered to add Salvia divinorum as a contributing factor, but no explanation was given for this (see below). In addition, according to some news stories, his mother Kathy Chidester does not blame Salvia divinorum exclusively for Chidester's death, but rather lists it as an unfortunate factor to an already deadly mix of causes. [2] ### Salvia divinorum Over three months after Chidester's suicide, with no evidence of any trace of salvinorin being found in his system, Delaware’s deputy chief medical examiner, Dr. Adrienne Sekula-Perlman, altered his death certificate to include Salvia divinorum use as a contributing cause of his death. She has subsequently refused to comment on her decision. [3] It is difficult to determine how much Salvia divinorum really contributed to the death of Chidester and the association with his suicide has been widely debated. Contrary to some news reports, his suicide note did not mention Salvia. Chidester had written about his experiences, and some published accounts have invited the inference they were written just prior to his death. His diary or journal entries said: Further context is lacking however as his journals have not been fully published. [4] While it has been alleged that the use of Salvia divinorum may have triggered in Chidester a depressional reaction leading to suicide, anectodal information suggests that Salvia divinorum acts instead as an anti-depressant. [5] Furthermore, Salvia divinorum is considered relatively non-toxic [6] (no lethal doses are known), non-addictive, short-acting (its effects lasting few minutes), with no significant deleterious long-term side-effects. There have been no other reported cases of Salvia divinorum related suicides (or accidental deaths) anywhere else in the world. It may be argued that this simply reflects Salvia’s relative obscurity, however, a simple Google search of 'Salvia divinorum' returns ~1,500,000 results[7] which is suggestive of Salvia’s fairly significant profile and repute. Due to the short acting effect of Salvia divinorum, lasting only few minutes, it is unlikely that Chidester was under the direct influence of the drug when he committed suicide. His parents knew he had experimented with Salvia divinorum and asked him to stop. He said he would discontinue using it, so it is uncertain if he was still taking the herb before his death. [8] Reports have not suggested in what form Chidester took the herb. A concentrated preparation of the leaf called Salvia extract, with relative strength suggested by terms such as 5x, 10x, 20x, even 30x, can be smoked in place of untreated leaves. It has yet to be established whether he was using natural leaf or a higher potency extract (and, if an extract, at what strength), or indeed if he was using any other form such as Salvia tincture. ### Alcohol The extent and significance of Chidester’s use of alcohol is a matter of contention. [9] Groups concerned with such issues report that the suicide rate for teenage drinkers is nearly twice as high as that for non-drinkers. [10] [11] Alcohol Concern’s suicide briefing details many points regarding the link between alcohol use and suicide, including: - Alcohol may be a factor in as many as 65% of suicide attempts (DoH 1993) - An international comparison found a clear association between alcohol consumption and suicide in 9 out of 13 countries studied (Lester 1995) - Alcohol misuse may lead to loss of self-esteem and hence to depression. These psychological changes may predispose someone to suicide (Kendall 1983) On April 20th 2006 Mothers Against Drunk Driving and Nationwide Mutual Insurance Company announced Gallup survey results on underage drinking. The results highlight a major public misperception regarding the severity of teen alcohol use. MADD's national president, Glynn R. Birch, said Chidester's death was reported locally by Delaware Online [13] and subsequently by a number of media outlets including CNN (links below), NBC [14], ABC [15], USAToday [16], W*USA 9 [17], KATV(Channel7) [18] and KXAN [19]. None of these or any other media stories on the issue have mentioned his alcohol use, all instead focusing on Salvia divinorum. ### Other risk factors Chidester was suffering from acne which has a general association with depression and thoughts of suicide [20][21] [22][23]. To treat his acne, he was also taking minocycline which can have side effects that may impair thinking or reactions [24]. His parents divorced when he was three. A study from the Research Data Centre program [25] published in the Journal of Marriage and Family found that children whose parents divorce show higher levels of depression, as well as higher levels of anti-social behaviour, than children whose parents remain married. [26] The parents have conceded that he may have been suffering from general depression. [27]	https://www.wikidoc.org/index.php/Brett%27s_law
95a9e93545500a8b15a9231f2efede77bba76e83	wikidoc	Brexanolone	Brexanolone # 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 Brexanolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator that is FDA approved for the treatment of postpartum depression (PPD) in adults. There is a Black Box Warning for this drug as shown here. Common adverse reactions include sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Brexanolone is indicated for the treatment of postpartum depression (PPD) in adults. Injection: 100 mg/20 mL (5 mg/mL) single-dose vial. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding brexanolone Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding brexanolone Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of brexanolone in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding brexanolone Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding brexanolone Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - In clinical studies, brexanolone caused sedation and somnolence that required dose interruption or reduction in some patients during the infusion (5% of brexanolone-treated patients compared to 0% of placebo-treated patients). Some patients were also reported to have loss of consciousness or altered state of consciousness during the brexanolone infusion (4% of the brexanolone-treated patients compared with 0% of the placebo-treated patients). Time to full recovery from loss or altered state of consciousness, after dose interruption, ranged from 15 to 60 minutes. A healthy 55-year-old man participating in a cardiac repolarization study experienced severe somnolence and <1 minute of apnea while receiving two times the maximum recommended dosage of brexanolone (180 mcg/kg/hour). All patients with loss of or altered state of consciousness recovered with dose interruption. - There was no clear association between loss or alteration of consciousness and pattern or timing of dose. Not all patients who experienced a loss or alteration of consciousness reported sedation or somnolence before the episode. - During the infusion, monitor patients for sedative effects every 2 hours during planned, non-sleep periods. Immediately stop the infusion if there are signs or symptoms of excessive sedation. - After symptoms resolve, the infusion may be resumed at the same or lower dose as clinically appropriate. - Immediately stop the infusion if pulse oximetry reveals hypoxia. After hypoxia, the infusion should not be resumed. - Patients should be cautioned against engaging in potentially hazardous activities requiring mental alertness, such as driving after infusion until any sedative effects of brexanolone have dissipated. Patients must be accompanied during interactions with their child(ren) while receiving the infusion because of the potential for excessive sedation and sudden loss of consciousness. - Concomitant use of opioids, antidepressants, or other CNS depressants such as benzodiazepines or alcohol may increase the likelihood or severity of adverse reactions related to sedation. - Because of the risk of serious harm resulting from excessive sedation or sudden loss of consciousness, brexanolone is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Zulresso REMS. - Brexanolone is available only through a restricted program under a REMS called the Zulresso REMS because excessive sedation or sudden loss of consciousness can result in serious harm. - Notable requirements of the Zulresso REMS include the following: Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to patients who are enrolled in the Zulresso REMS. Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the Zulresso REMS. Patients must be enrolled in the Zulresso REMS prior to administration of brexanolone. Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies. - Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to patients who are enrolled in the Zulresso REMS. - Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the Zulresso REMS. - Patients must be enrolled in the Zulresso REMS prior to administration of brexanolone. - Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies. - Further information, including a list of certified healthcare facilities, is available at WWW.ZULRESSOREMS.COM or 1-844-472-4379. - In pooled analyses of placebo-controlled trials of chronically administered antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with major depressive disorder (MDD). The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in TABLE 1. - Brexanolone does not directly affect monoaminergic systems. Because of this and the comparatively low number of exposures to brexanolone, the risk of developing suicidal thoughts and behaviors with brexanolone is unknown. Consider changing the therapeutic regimen, including discontinuing brexanolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 brexanolone in 140 patients with postpartum depression (PPD). A titration to a target dosage of 90 mcg/kg/hour was evaluated in 102 patients and a titration to a target dose of 60 mcg/kg/hour was evaluated in 38 patients. Patients were then followed for 4 weeks. - The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush (TABLE 2). Adverse Reactions Leading to Discontinuation, Dosage Interruption, or Dosage Reduction - In the pooled placebo controlled-studies, the incidence of patients who discontinued due to any adverse reaction was 2% of brexanolone-treated patients compared to 1% of placebo-treated patients. The adverse reactions leading to treatment discontinuation in brexanolone-treated patients were sedation-related (loss of consciousness, vertigo, syncope, and presyncope) or infusion site pain. - In the pooled placebo controlled-studies, the incidence of patients who had an interruption or reduction of the dosage due to any adverse reaction was 7% of brexanolone-treated patients compared to 3% of placebo-treated patients. The adverse reactions leading to dose reduction or interruption in brexanolone-treated patients were sedation-related (loss of consciousness, syncope, somnolence, dizziness, fatigue), infusion site events, changes in blood pressure, or medication error due to infusion pump malfunction. Three brexanolone-treated patients who had a dosage interruption because of loss of consciousness subsequently resumed and completed treatment after resolution of symptoms; two patients who had dosage interruption because of loss of consciousness did not resume the infusion. - TABLE 2 presents the adverse reactions that occurred in brexanolone-treated PPD patients at a rate of at least 2% and at a higher rate than in the placebo-treated patients during the 60-hour treatment period. ## Postmarketing Experience There is limited information regarding Brexanolone Postmarketing Experience in the drug label. # Drug Interactions - Concomitant use of brexanolone with CNS depressants (e.g., opioids, benzodiazepines) may increase the likelihood or severity of adverse reactions related to sedation. - In the placebo-controlled studies, a higher percentage of brexanolone-treated patients who used concomitant antidepressants reported sedation-related events. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Exposure - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at HTTPS/. Risk Summary - Based on findings from animal studies of other drugs that enhance GABAergic inhibition, brexanolone may cause fetal harm. There are no available data on brexanolone use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, malformations were not seen in rats or rabbits at plasma levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively. Developmental toxicities were seen in the fetuses of rats and rabbits at 5 and ≥3 times the plasma levels at the MRHD, respectively. Reproductive toxicities were seen in rabbits at ≥3 times the plasma levels at the MRHD. These effects were not seen in rats and rabbits at 2 and 1.2 times the plasma levels at the MRHD. Brexanolone administered to pregnant rats during pregnancy and lactation resulted in lower pup survival at doses which were associated with ≥2 times the plasma levels at the MRHD and a neurobehavioral deficit in female offspring at 5 times the plasma levels at the MRHD. These effects were not seen at 0.8 times and 2 times the plasma levels at the MRHD, respectively. - In published animal studies, administration of other drugs that enhance GABAergic inhibition to neonatal rats caused widespread apoptotic neurodegeneration in the developing brain. The window of vulnerability to these changes in rats (postnatal days 0-14) corresponds to the period of brain development that takes place during the third trimester of pregnancy in humans. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. 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. Animal Data - In pregnant rats and rabbits, no malformations were seen when brexanolone was given during the period of organogenesis at continuous intravenous doses up to 60 and 30 mg/kg/day, respectively. These doses were associated with maternal plasma levels 5 and 6 times the plasma levels at the MRHD of 90 mcg/kg/hour, in rats and rabbits, respectively. In rats, a decrease in fetal body weights was seen at 60 mg/kg/day (5 times the plasma level at the MRHD). In rabbits, increased numbers of late resorptions and a decrease in fetal body weights were seen at doses equal to and greater than 15 mg/kg/day (3 times the plasma levels at the MRHD) with fewer live fetuses and a higher post implantation loss seen at 30 mg/kg/day (6 times the plasma levels at the MRHD) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain and/or body weight loss). Effects in rats and rabbits were not seen at 2 and 1.2 times the plasma levels at the MRHD, respectively. - When brexanolone was administered to pregnant rats by continuous intravenous administration at 30 and 60 mg/kg/day (2 and 5 times plasma levels at the MRHD, respectively) during the period of organogenesis and throughout pregnancy and lactation, increased numbers of dead pups and fewer live pups at birth were seen. This effect was not seen at 0.8 times the plasma levels at the MRHD. Decreased pup viability between postnatal day 0 and 4 in the presence of maternal toxicity (decreased body weight gain and food consumption during lactation) was seen at 5 times the plasma levels at the MRHD. These effects were not seen at 2 times the plasma levels at the MRHD. A neurobehavioral deficit, characterized by slower habituation in the maximal startle response in the auditory startle test, was seen in female offspring of dams dosed at 5 times the plasma levels at the MRHD. This effect was not seen at 2 times the plasma levels at the MRHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brexanolone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Brexanolone during labor and delivery. ### Nursing Mothers Risk Summary - Available data from a lactation study in 12 women indicate that brexanolone is transferred to breastmilk in nursing mothers. However, the relative infant dose (RID) is low, 1% to 2% of the maternal weight-adjusted dosage (see DATA). Also, as brexanolone has low oral bioavailability (<5%) in adults, infant exposure is expected to be low. There were no reports of effects of brexanolone on milk production. There are no data on the effects of brexanolone on a breastfed infant. Available data on the use of brexanolone during lactation do not suggest a significant risk of adverse reactions to breastfed infants from exposure to brexanolone. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for brexanolone and any potential adverse effects on the breastfed child from brexanolone or from the underlying maternal condition. Data - A study was conducted in twelve healthy adult lactating women treated with intravenous brexanolone according to the recommended 60-hour dosing regimen (maximum dosage was 90 mcg/kg/hour). Concentrations of brexanolone in breast milk were at low levels (95% of women by 36 hours after the end of the infusion of brexanolone. The calculated maximum relative infant dose for brexanolone during the infusion was 1% to 2%. ### Pediatric Use - The safety and effectiveness of brexanolone in pediatric patients have not been established. ### Geriatic Use PPD is a condition associated with pregnancy; there is no geriatric experience with brexanolone. ### Gender There is no FDA guidance on the use of Brexanolone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Brexanolone with respect to specific racial populations. ### Renal Impairment - No dosage adjustment is recommended in patients with mild (eGFR 60 to 89 mL/minute/1.73 m2), moderate (eGFR 30 to 59 mL/minute/1.73 m2) or severe (eGFR 15 to 29 mL/minute/1.73 m2) renal impairment. - Avoid use of brexanolone in patients with end stage renal disease (ESRD) with eGFR of < 15 mL/minute/1.73 m2 because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium. ### Hepatic Impairment - Dosage adjustment in patients with hepatic impairment is not necessary. Modest increases in exposure to unbound brexanolone and modest decreases in exposure to total brexanolone were observed in patients with moderate to severe hepatic impairment (Child-Pugh≥7) with no associated change in tolerability. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Brexanolone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Brexanolone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administer brexanolone as a continuous intravenous (IV) infusion over a total of 60 hours (2.5 days) as follows: 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour 4 to 24 hours: Increase dosage to 60 mcg/kg/hour 24 to 52 hours: Increase dosage to 90 mcg/kg/hour (a reduction in dosage to 60 mcg/kg/hour may be considered during this time period for patients who do not tolerate 90 mcg/kg/hour) 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour - 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour - 4 to 24 hours: Increase dosage to 60 mcg/kg/hour - 24 to 52 hours: Increase dosage to 90 mcg/kg/hour (a reduction in dosage to 60 mcg/kg/hour may be considered during this time period for patients who do not tolerate 90 mcg/kg/hour) - 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour - 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour - If excessive sedation occurs at any time during the infusion, stop the infusion until the symptoms resolve. The infusion may be resumed at the same or lower dose as clinically appropriate. - Brexanolone is supplied in vials as a concentrated solution that requires dilution prior to administration. After dilution, the product can be stored in infusion bags under refrigerated conditions for up to 96 hours. However, given that the diluted product can be used for only 12 hours at room temperature, each 60-hour infusion will require the preparation of at least five infusion bags. - Prepare according to the following steps using aseptic technique: Visually inspect the vials of brexanolone for particulate matter and discoloration prior to administration. Brexanolone is a clear, colorless solution. Do not use if the solution is discolored or particulate matter is present. The 60-hour infusion will generally require the preparation of five infusion bags. Additional bags will be needed for patients weighing ≥ 90 kg. For each infusion bag: Prepare and store in a polyolefin, non-DEHP, nonlatex bag, only. Dilute in the infusion bag immediately after the initial puncture of the drug product vial. Withdraw 20 mL of brexanolone from the vial and place in the infusion bag. Dilute with 40 mL of Sterile Water for Injection, and further dilute with 40 mL of 0.9% Sodium Chloride Injection (total volume of 100 mL) to achieve a target concentration of 1 mg/mL. Immediately place the infusion bag under refrigerated conditions until use. - Visually inspect the vials of brexanolone for particulate matter and discoloration prior to administration. Brexanolone is a clear, colorless solution. Do not use if the solution is discolored or particulate matter is present. - The 60-hour infusion will generally require the preparation of five infusion bags. Additional bags will be needed for patients weighing ≥ 90 kg. - For each infusion bag: Prepare and store in a polyolefin, non-DEHP, nonlatex bag, only. Dilute in the infusion bag immediately after the initial puncture of the drug product vial. Withdraw 20 mL of brexanolone from the vial and place in the infusion bag. Dilute with 40 mL of Sterile Water for Injection, and further dilute with 40 mL of 0.9% Sodium Chloride Injection (total volume of 100 mL) to achieve a target concentration of 1 mg/mL. Immediately place the infusion bag under refrigerated conditions until use. - Prepare and store in a polyolefin, non-DEHP, nonlatex bag, only. Dilute in the infusion bag immediately after the initial puncture of the drug product vial. - Withdraw 20 mL of brexanolone from the vial and place in the infusion bag. Dilute with 40 mL of Sterile Water for Injection, and further dilute with 40 mL of 0.9% Sodium Chloride Injection (total volume of 100 mL) to achieve a target concentration of 1 mg/mL. - Immediately place the infusion bag under refrigerated conditions until use. - Diluted brexanolone storage instructions: If not used immediately after dilution, store under refrigerated conditions for up to 96 hours. Prolonged storage at room temperature may support adventitious microbial growth. Each prepared bag of diluted brexanolone may be used for up to 12 hours of infusion time at room temperature. Discard any unused brexanolone after 12 hours of infusion. - If not used immediately after dilution, store under refrigerated conditions for up to 96 hours. Prolonged storage at room temperature may support adventitious microbial growth. - Each prepared bag of diluted brexanolone may be used for up to 12 hours of infusion time at room temperature. Discard any unused brexanolone after 12 hours of infusion. - Brexanolone must be diluted before administration. The following are important administration instructions: Use a programmable peristaltic infusion pump to ensure accurate delivery of brexanolone. Administer brexanolone via a dedicated line. Do not inject other medications into the infusion bag or mix with brexanolone. Fully prime infusion administration sets with admixture before inserting into the pump and connecting to the venous catheter. Use a PVC, non-DEHP, nonlatex infusion set. Do not use in-line filter infusion sets. - Use a programmable peristaltic infusion pump to ensure accurate delivery of brexanolone. - Administer brexanolone via a dedicated line. Do not inject other medications into the infusion bag or mix with brexanolone. - Fully prime infusion administration sets with admixture before inserting into the pump and connecting to the venous catheter. - Use a PVC, non-DEHP, nonlatex infusion set. Do not use in-line filter infusion sets. - Avoid use of brexanolone in patients with end stage renal disease (ESRD) with eGFR of < 15 mL/minute/1.73 m2 because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium. ### Monitoring Important Considerations Prior to Initiating and During Therapy - A healthcare provider must be available on site to continuously monitor the patient, and intervene as necessary, for the duration of the brexanolone infusion. - Monitor patients for hypoxia using continuous pulse oximetry equipped with an alarm. Assess for excessive sedation every 2 hours during planned, non-sleep periods. - Initiate brexanolone treatment early enough during the day to allow for recognition of excessive sedation. # IV Compatibility - Brexanolone is administered as a continuous intravenous (IV) infusion over a total of 60 hours (2.5 days). # Overdosage Human Experience - There is limited clinical trial experience regarding human overdosage with brexanolone. In premarketing clinical studies, two cases of accidental overdosage due to infusion pump malfunction resulted in transient loss of consciousness. Both patients regained consciousness approximately 15 minutes after discontinuation of the infusion without supportive measures. After full resolution of symptoms, both patients subsequently resumed and completed treatment. Overdosage may result in excessive sedation, including loss of consciousness and the potential for accompanying respiratory changes. Management of Overdose - In case of overdosage, stop the infusion immediately and initiate supportive measures as necessary. Brexanolone is rapidly cleared from plasma. Consult a Certified Poison Control Center at 1-800-222-1222 for latest recommendations. # Pharmacology ## Mechanism of Action - The mechanism of action of brexanolone in the treatment of PPD in adults is not fully understood, but is thought to be related to its positive allosteric modulation of GABAA receptors. ## Structure The molecular formula of brexanolone is C21H34O2. The relative molecular mass is 318.5 Da. ## Pharmacodynamics - Brexanolone potentiated GABA-mediated currents from recombinant human GABAA receptors in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits. - Brexanolone exposure-response relationships and the time course of pharmacodynamics response are unknown. Cardiac Electrophysiology - The effect of brexanolone on the QT interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, three-period crossover thorough QT study in 30 healthy adult subjects. At 1.9-times the exposure occurring at the highest recommended infusion rate (90 mcg/kg/hour), brexanolone did not prolong the QT interval to a clinically relevant extent. ## Pharmacokinetics - Brexanolone exhibited dose proportional pharmacokinetics over a dosage range of 30 mcg/kg/hour to 270 mcg/kg/hour (three times the maximum recommended dosage). Mean steady state exposure at 60 mcg/kg/hour and 90 mcg/kg/hour was around 52 ng/mL and 79 ng/mL, respectively. Distribution - The volume of distribution of brexanolone was approximately 3 L/kg, suggesting extensive distribution into tissues. Plasma protein binding was greater than 99% and is independent of plasma concentrations. Elimination - The terminal half-life of brexanolone is approximately 9 hours. The total plasma clearance of brexanolone is approximately 1 L/h/kg. Metabolism - Brexanolone is extensively metabolized by non-CYP based pathways via three main routes - keto-reduction (AKRs), glucuronidation (UGTs), and sulfation (SULTs). There are three major circulating metabolites that are pharmacologically inactive and do not contribute to the overall efficacy of brexanolone. Excretion - Following administration of radiolabeled brexanolone, 47% was recovered in feces (primarily as metabolites) and 42% in urine (with less than 1% as unchanged brexanolone). Specific Populations - No clinically significant differences in the pharmacokinetics of brexanolone were observed based on renal impairment (severe) study or hepatic impairment (mild, moderate, severe) study. The effect of end stage renal disease (ESRD, eGFR < 15 mL/minute/1.73 m2) on brexanolone pharmacokinetics is unknown. However, avoid use of brexanolone in patients with ESRD. Drug Interaction Studies - No studies were conducted to evaluate the effects of other drugs on brexanolone. - No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when it was used concomitantly with brexanolone. Betadex Sulfobutyl Ether Sodium Pharmacokinetics - Betadex sulfobutyl ether sodium is a solubilizing agent in brexanolone. In patients with severe renal impairment (eGFR 15-29 mL/minute/1.73 m2), betadex sulfobutyl ether sodium AUCinf increased 5.5-fold and Cmax increased 1.7-fold. Avoid use of brexanolone in patients with ESRD. ## Nonclinical Toxicology Carcinogenesis - Carcinogenicity studies of brexanolone have not been performed. Mutagenesis - Brexanolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay. Impairment of Fertility - Treatment of female and male rats with brexanolone at doses equal to and greater than 30 mg/kg/day, which is associated with 2 times the plasma levels at the maximum recommended human dose (MRHD) of 90 mcg/kg/hour, caused impairment of female and male fertility and reproduction. In female rats, brexanolone was associated with decreased mating and fertility indices, an increase in number of days to mating, prolonged/irregular estrous cycles, an increase in the number of early resorptions, and post implantation loss. Reversal of effects in females was observed following a 28-day recovery period. In male rats, brexanolone was associated with decreased mating and fertility indices, decreased conception rate, lower prostate, seminal vesicle, and epididymis weight, as well as decreased sperm numbers. Impaired female and male fertility and reproduction were not observed at 0.8 times the MRHD. # Clinical Studies - The efficacy of brexanolone in the treatment of postpartum depression (PPD) was demonstrated in two multicenter, randomized, double-blind, placebo-controlled studies (referred to as Studies 1 and 2) in women (18 to 45 years) with PPD who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode (DSM-IV) with onset of symptoms in the third trimester or within 4 weeks of delivery. In these studies, patients received a 60-hour continuous intravenous infusion of brexanolone or placebo and were then followed for 4 weeks. Study 1 (NCT02942004) included patients with severe PPD (Hamilton Depression Rating Scale (HAM-D) score ≥ 26), and Study 2 (NCT02942017) included patients with moderate PPD (HAM-D score of 20 to 25). A titration to the recommended target dosage of 90 mcg/kg/hour was evaluated in both studies (patients received 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for 20 hours, 90 mcg/kg/hour for 28 hours, followed by a taper to 60 mcg/kg/hour for 4 hours and then 30 mcg/kg/hour for 4 hours). A titration to a target dosage of 60 mcg/kg/hour (patients received 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for 52 hours, then 30 mcg/kg/hour for 4 hours) was also evaluated in Study 1. - Demographic and baseline disease characteristics were generally similar across treatment groups in the pooled Studies 1 and 2. Most patients were White (63%) or Black (34%); 18% of patients identified as Hispanic or Latina; the average age of women receiving brexanolone was 28 years. Most patients (76%) had onset of PPD symptoms within 4 weeks after delivery, with the remainder having onset during the third trimester. Baseline oral antidepressant use was reported for 23% of patients. - The primary endpoint was the mean change from baseline in depressive symptoms as measured by the HAM-D total score at the end of the infusion (Hour 60). A pre-specified secondary efficacy endpoint was the mean change from baseline in HAM-D total score at Day 30. In both placebo-controlled studies, titration to a target dose of brexanolone 90 mcg/kg/hour was superior to placebo in improvement of depressive symptoms. In a group of 38 patients in Study 1, a brexanolone titration to a target dose of 60 mcg/kg/hour was also superior to placebo in improvement of depressive symptoms. - Examination of subgroups by race did not suggest differences in response. Time Course of Treatment Response - FIGURE 1 shows the time course of response for the brexanolone 90 mcg/kg/hour-target and 60 mcg/kg/hour-target groups compared to the placebo group for Study 1. # How Supplied - Brexanolone injection is supplied as 100 mg brexanolone in 20 mL (5 mg/mL) single-dose vials containing a sterile, preservative-free, clear, colorless solution. ## Storage - Store the undiluted brexanolone product at 2°C to 8°C (36°F to 46°F). Do not freeze. Store protected from light. - The diluted product in the infusion bag can be used at room temperature for up to 12 hours. If the diluted product is not used immediately after dilution, store under refrigerated conditions for up to 96 hours. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE). Excessive Sedation and Sudden Loss of Consciousness - Patients may experience loss of consciousness or altered state of consciousness during the brexanolone infusion. Advise patients to report signs of excessive sedation that may occur during the infusion. Patients must not be the primary caregiver of dependents and must be accompanied during interactions with their child(red). Zulresso Risk Evaluation and Mitigation Strategy (REMS) - Brexanolone is available only through a restricted program called the Zulresso REMS. - Inform the patient of the following notable requirements: Patients must be enrolled in the Zulresso REMS Program prior to administration. Patients must be monitored during administration of brexanolone and report any signs and symptoms of excessive sedation to a healthcare provider. - Patients must be enrolled in the Zulresso REMS Program prior to administration. - Patients must be monitored during administration of brexanolone and report any signs and symptoms of excessive sedation to a healthcare provider. Potential for Abuse - Advise patients that brexanolone can be abused or lead to dependence. Concomitant Medications - Caution patients that opioids or other CNS depressants, such as benzodiazepines, taken in combination with brexanolone may increase the severity of sedative effects. Suicide Thoughts and Behaviors - Advise patients and caregivers to look for the emergence of suicidal thoughts and behavior and instruct them to report such symptoms to the healthcare provider. Pregnancy - Advise women to notify their healthcare provider if they could possibly be pregnant prior to therapy with brexanolone. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to brexanolone during pregnancy. # Precautions with Alcohol - Concomitant use of alcohol may increase the likelihood or severity of adverse reactions related to sedation. # Brand Names Zulresso # Look-Alike Drug Names There is limited information regarding Brexanolone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Brexanolone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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 Brexanolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator that is FDA approved for the treatment of postpartum depression (PPD) in adults. There is a Black Box Warning for this drug as shown here. Common adverse reactions include sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Brexanolone is indicated for the treatment of postpartum depression (PPD) in adults. Injection: 100 mg/20 mL (5 mg/mL) single-dose vial. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding brexanolone Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding brexanolone Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of brexanolone in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding brexanolone Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding brexanolone Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications None. # Warnings - In clinical studies, brexanolone caused sedation and somnolence that required dose interruption or reduction in some patients during the infusion (5% of brexanolone-treated patients compared to 0% of placebo-treated patients). Some patients were also reported to have loss of consciousness or altered state of consciousness during the brexanolone infusion (4% of the brexanolone-treated patients compared with 0% of the placebo-treated patients). Time to full recovery from loss or altered state of consciousness, after dose interruption, ranged from 15 to 60 minutes. A healthy 55-year-old man participating in a cardiac repolarization study experienced severe somnolence and <1 minute of apnea while receiving two times the maximum recommended dosage of brexanolone (180 mcg/kg/hour). All patients with loss of or altered state of consciousness recovered with dose interruption. - There was no clear association between loss or alteration of consciousness and pattern or timing of dose. Not all patients who experienced a loss or alteration of consciousness reported sedation or somnolence before the episode. - During the infusion, monitor patients for sedative effects every 2 hours during planned, non-sleep periods. Immediately stop the infusion if there are signs or symptoms of excessive sedation. - After symptoms resolve, the infusion may be resumed at the same or lower dose as clinically appropriate. - Immediately stop the infusion if pulse oximetry reveals hypoxia. After hypoxia, the infusion should not be resumed. - Patients should be cautioned against engaging in potentially hazardous activities requiring mental alertness, such as driving after infusion until any sedative effects of brexanolone have dissipated. Patients must be accompanied during interactions with their child(ren) while receiving the infusion because of the potential for excessive sedation and sudden loss of consciousness. - Concomitant use of opioids, antidepressants, or other CNS depressants such as benzodiazepines or alcohol may increase the likelihood or severity of adverse reactions related to sedation. - Because of the risk of serious harm resulting from excessive sedation or sudden loss of consciousness, brexanolone is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Zulresso REMS. - Brexanolone is available only through a restricted program under a REMS called the Zulresso REMS because excessive sedation or sudden loss of consciousness can result in serious harm. - Notable requirements of the Zulresso REMS include the following: Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to patients who are enrolled in the Zulresso REMS. Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the Zulresso REMS. Patients must be enrolled in the Zulresso REMS prior to administration of brexanolone. Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies. - Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to patients who are enrolled in the Zulresso REMS. - Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the Zulresso REMS. - Patients must be enrolled in the Zulresso REMS prior to administration of brexanolone. - Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies. - Further information, including a list of certified healthcare facilities, is available at WWW.ZULRESSOREMS.COM or 1-844-472-4379. - In pooled analyses of placebo-controlled trials of chronically administered antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with major depressive disorder (MDD). The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in TABLE 1. - Brexanolone does not directly affect monoaminergic systems. Because of this and the comparatively low number of exposures to brexanolone, the risk of developing suicidal thoughts and behaviors with brexanolone is unknown. Consider changing the therapeutic regimen, including discontinuing brexanolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 brexanolone in 140 patients with postpartum depression (PPD). A titration to a target dosage of 90 mcg/kg/hour was evaluated in 102 patients and a titration to a target dose of 60 mcg/kg/hour was evaluated in 38 patients. Patients were then followed for 4 weeks. - The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush (TABLE 2). Adverse Reactions Leading to Discontinuation, Dosage Interruption, or Dosage Reduction - In the pooled placebo controlled-studies, the incidence of patients who discontinued due to any adverse reaction was 2% of brexanolone-treated patients compared to 1% of placebo-treated patients. The adverse reactions leading to treatment discontinuation in brexanolone-treated patients were sedation-related (loss of consciousness, vertigo, syncope, and presyncope) or infusion site pain. - In the pooled placebo controlled-studies, the incidence of patients who had an interruption or reduction of the dosage due to any adverse reaction was 7% of brexanolone-treated patients compared to 3% of placebo-treated patients. The adverse reactions leading to dose reduction or interruption in brexanolone-treated patients were sedation-related (loss of consciousness, syncope, somnolence, dizziness, fatigue), infusion site events, changes in blood pressure, or medication error due to infusion pump malfunction. Three brexanolone-treated patients who had a dosage interruption because of loss of consciousness subsequently resumed and completed treatment after resolution of symptoms; two patients who had dosage interruption because of loss of consciousness did not resume the infusion. - TABLE 2 presents the adverse reactions that occurred in brexanolone-treated PPD patients at a rate of at least 2% and at a higher rate than in the placebo-treated patients during the 60-hour treatment period. ## Postmarketing Experience There is limited information regarding Brexanolone Postmarketing Experience in the drug label. # Drug Interactions - Concomitant use of brexanolone with CNS depressants (e.g., opioids, benzodiazepines) may increase the likelihood or severity of adverse reactions related to sedation. - In the placebo-controlled studies, a higher percentage of brexanolone-treated patients who used concomitant antidepressants reported sedation-related events. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Exposure - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at HTTPS://WOMENSMENTALHEALTH.ORG/CLINICAL-AND-RESEARCH-PROGRAMS/PREGNANCYREGISTRY/ANTIDEPRESSANTS/. Risk Summary - Based on findings from animal studies of other drugs that enhance GABAergic inhibition, brexanolone may cause fetal harm. There are no available data on brexanolone use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, malformations were not seen in rats or rabbits at plasma levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively. Developmental toxicities were seen in the fetuses of rats and rabbits at 5 and ≥3 times the plasma levels at the MRHD, respectively. Reproductive toxicities were seen in rabbits at ≥3 times the plasma levels at the MRHD. These effects were not seen in rats and rabbits at 2 and 1.2 times the plasma levels at the MRHD. Brexanolone administered to pregnant rats during pregnancy and lactation resulted in lower pup survival at doses which were associated with ≥2 times the plasma levels at the MRHD and a neurobehavioral deficit in female offspring at 5 times the plasma levels at the MRHD. These effects were not seen at 0.8 times and 2 times the plasma levels at the MRHD, respectively. - In published animal studies, administration of other drugs that enhance GABAergic inhibition to neonatal rats caused widespread apoptotic neurodegeneration in the developing brain. The window of vulnerability to these changes in rats (postnatal days 0-14) corresponds to the period of brain development that takes place during the third trimester of pregnancy in humans. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. 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. Animal Data - In pregnant rats and rabbits, no malformations were seen when brexanolone was given during the period of organogenesis at continuous intravenous doses up to 60 and 30 mg/kg/day, respectively. These doses were associated with maternal plasma levels 5 and 6 times the plasma levels at the MRHD of 90 mcg/kg/hour, in rats and rabbits, respectively. In rats, a decrease in fetal body weights was seen at 60 mg/kg/day (5 times the plasma level at the MRHD). In rabbits, increased numbers of late resorptions and a decrease in fetal body weights were seen at doses equal to and greater than 15 mg/kg/day (3 times the plasma levels at the MRHD) with fewer live fetuses and a higher post implantation loss seen at 30 mg/kg/day (6 times the plasma levels at the MRHD) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain and/or body weight loss). Effects in rats and rabbits were not seen at 2 and 1.2 times the plasma levels at the MRHD, respectively. - When brexanolone was administered to pregnant rats by continuous intravenous administration at 30 and 60 mg/kg/day (2 and 5 times plasma levels at the MRHD, respectively) during the period of organogenesis and throughout pregnancy and lactation, increased numbers of dead pups and fewer live pups at birth were seen. This effect was not seen at 0.8 times the plasma levels at the MRHD. Decreased pup viability between postnatal day 0 and 4 in the presence of maternal toxicity (decreased body weight gain and food consumption during lactation) was seen at 5 times the plasma levels at the MRHD. These effects were not seen at 2 times the plasma levels at the MRHD. A neurobehavioral deficit, characterized by slower habituation in the maximal startle response in the auditory startle test, was seen in female offspring of dams dosed at 5 times the plasma levels at the MRHD. This effect was not seen at 2 times the plasma levels at the MRHD. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brexanolone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Brexanolone during labor and delivery. ### Nursing Mothers Risk Summary - Available data from a lactation study in 12 women indicate that brexanolone is transferred to breastmilk in nursing mothers. However, the relative infant dose (RID) is low, 1% to 2% of the maternal weight-adjusted dosage (see DATA). Also, as brexanolone has low oral bioavailability (<5%) in adults, infant exposure is expected to be low. There were no reports of effects of brexanolone on milk production. There are no data on the effects of brexanolone on a breastfed infant. Available data on the use of brexanolone during lactation do not suggest a significant risk of adverse reactions to breastfed infants from exposure to brexanolone. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for brexanolone and any potential adverse effects on the breastfed child from brexanolone or from the underlying maternal condition. Data - A study was conducted in twelve healthy adult lactating women treated with intravenous brexanolone according to the recommended 60-hour dosing regimen (maximum dosage was 90 mcg/kg/hour). Concentrations of brexanolone in breast milk were at low levels (<10 ng/mL) in >95% of women by 36 hours after the end of the infusion of brexanolone. The calculated maximum relative infant dose for brexanolone during the infusion was 1% to 2%. ### Pediatric Use - The safety and effectiveness of brexanolone in pediatric patients have not been established. ### Geriatic Use PPD is a condition associated with pregnancy; there is no geriatric experience with brexanolone. ### Gender There is no FDA guidance on the use of Brexanolone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Brexanolone with respect to specific racial populations. ### Renal Impairment - No dosage adjustment is recommended in patients with mild (eGFR 60 to 89 mL/minute/1.73 m2), moderate (eGFR 30 to 59 mL/minute/1.73 m2) or severe (eGFR 15 to 29 mL/minute/1.73 m2) renal impairment. - Avoid use of brexanolone in patients with end stage renal disease (ESRD) with eGFR of < 15 mL/minute/1.73 m2 because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium. ### Hepatic Impairment - Dosage adjustment in patients with hepatic impairment is not necessary. Modest increases in exposure to unbound brexanolone and modest decreases in exposure to total brexanolone were observed in patients with moderate to severe hepatic impairment (Child-Pugh≥7) with no associated change in tolerability. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Brexanolone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Brexanolone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administer brexanolone as a continuous intravenous (IV) infusion over a total of 60 hours (2.5 days) as follows: 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour 4 to 24 hours: Increase dosage to 60 mcg/kg/hour 24 to 52 hours: Increase dosage to 90 mcg/kg/hour (a reduction in dosage to 60 mcg/kg/hour may be considered during this time period for patients who do not tolerate 90 mcg/kg/hour) 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour - 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour - 4 to 24 hours: Increase dosage to 60 mcg/kg/hour - 24 to 52 hours: Increase dosage to 90 mcg/kg/hour (a reduction in dosage to 60 mcg/kg/hour may be considered during this time period for patients who do not tolerate 90 mcg/kg/hour) - 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour - 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour - If excessive sedation occurs at any time during the infusion, stop the infusion until the symptoms resolve. The infusion may be resumed at the same or lower dose as clinically appropriate. - Brexanolone is supplied in vials as a concentrated solution that requires dilution prior to administration. After dilution, the product can be stored in infusion bags under refrigerated conditions for up to 96 hours. However, given that the diluted product can be used for only 12 hours at room temperature, each 60-hour infusion will require the preparation of at least five infusion bags. - Prepare according to the following steps using aseptic technique: Visually inspect the vials of brexanolone for particulate matter and discoloration prior to administration. Brexanolone is a clear, colorless solution. Do not use if the solution is discolored or particulate matter is present. The 60-hour infusion will generally require the preparation of five infusion bags. Additional bags will be needed for patients weighing ≥ 90 kg. For each infusion bag: Prepare and store in a polyolefin, non-DEHP, nonlatex bag, only. Dilute in the infusion bag immediately after the initial puncture of the drug product vial. Withdraw 20 mL of brexanolone from the vial and place in the infusion bag. Dilute with 40 mL of Sterile Water for Injection, and further dilute with 40 mL of 0.9% Sodium Chloride Injection (total volume of 100 mL) to achieve a target concentration of 1 mg/mL. Immediately place the infusion bag under refrigerated conditions until use. - Visually inspect the vials of brexanolone for particulate matter and discoloration prior to administration. Brexanolone is a clear, colorless solution. Do not use if the solution is discolored or particulate matter is present. - The 60-hour infusion will generally require the preparation of five infusion bags. Additional bags will be needed for patients weighing ≥ 90 kg. - For each infusion bag: Prepare and store in a polyolefin, non-DEHP, nonlatex bag, only. Dilute in the infusion bag immediately after the initial puncture of the drug product vial. Withdraw 20 mL of brexanolone from the vial and place in the infusion bag. Dilute with 40 mL of Sterile Water for Injection, and further dilute with 40 mL of 0.9% Sodium Chloride Injection (total volume of 100 mL) to achieve a target concentration of 1 mg/mL. Immediately place the infusion bag under refrigerated conditions until use. - Prepare and store in a polyolefin, non-DEHP, nonlatex bag, only. Dilute in the infusion bag immediately after the initial puncture of the drug product vial. - Withdraw 20 mL of brexanolone from the vial and place in the infusion bag. Dilute with 40 mL of Sterile Water for Injection, and further dilute with 40 mL of 0.9% Sodium Chloride Injection (total volume of 100 mL) to achieve a target concentration of 1 mg/mL. - Immediately place the infusion bag under refrigerated conditions until use. - Diluted brexanolone storage instructions: If not used immediately after dilution, store under refrigerated conditions for up to 96 hours. Prolonged storage at room temperature may support adventitious microbial growth. Each prepared bag of diluted brexanolone may be used for up to 12 hours of infusion time at room temperature. Discard any unused brexanolone after 12 hours of infusion. - If not used immediately after dilution, store under refrigerated conditions for up to 96 hours. Prolonged storage at room temperature may support adventitious microbial growth. - Each prepared bag of diluted brexanolone may be used for up to 12 hours of infusion time at room temperature. Discard any unused brexanolone after 12 hours of infusion. - Brexanolone must be diluted before administration. The following are important administration instructions: Use a programmable peristaltic infusion pump to ensure accurate delivery of brexanolone. Administer brexanolone via a dedicated line. Do not inject other medications into the infusion bag or mix with brexanolone. Fully prime infusion administration sets with admixture before inserting into the pump and connecting to the venous catheter. Use a PVC, non-DEHP, nonlatex infusion set. Do not use in-line filter infusion sets. - Use a programmable peristaltic infusion pump to ensure accurate delivery of brexanolone. - Administer brexanolone via a dedicated line. Do not inject other medications into the infusion bag or mix with brexanolone. - Fully prime infusion administration sets with admixture before inserting into the pump and connecting to the venous catheter. - Use a PVC, non-DEHP, nonlatex infusion set. Do not use in-line filter infusion sets. - Avoid use of brexanolone in patients with end stage renal disease (ESRD) with eGFR of < 15 mL/minute/1.73 m2 because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium. ### Monitoring Important Considerations Prior to Initiating and During Therapy - A healthcare provider must be available on site to continuously monitor the patient, and intervene as necessary, for the duration of the brexanolone infusion. - Monitor patients for hypoxia using continuous pulse oximetry equipped with an alarm. Assess for excessive sedation every 2 hours during planned, non-sleep periods. - Initiate brexanolone treatment early enough during the day to allow for recognition of excessive sedation. # IV Compatibility - Brexanolone is administered as a continuous intravenous (IV) infusion over a total of 60 hours (2.5 days). # Overdosage Human Experience - There is limited clinical trial experience regarding human overdosage with brexanolone. In premarketing clinical studies, two cases of accidental overdosage due to infusion pump malfunction resulted in transient loss of consciousness. Both patients regained consciousness approximately 15 minutes after discontinuation of the infusion without supportive measures. After full resolution of symptoms, both patients subsequently resumed and completed treatment. Overdosage may result in excessive sedation, including loss of consciousness and the potential for accompanying respiratory changes. Management of Overdose - In case of overdosage, stop the infusion immediately and initiate supportive measures as necessary. Brexanolone is rapidly cleared from plasma. Consult a Certified Poison Control Center at 1-800-222-1222 for latest recommendations. # Pharmacology ## Mechanism of Action - The mechanism of action of brexanolone in the treatment of PPD in adults is not fully understood, but is thought to be related to its positive allosteric modulation of GABAA receptors. ## Structure The molecular formula of brexanolone is C21H34O2. The relative molecular mass is 318.5 Da. ## Pharmacodynamics - Brexanolone potentiated GABA-mediated currents from recombinant human GABAA receptors in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits. - Brexanolone exposure-response relationships and the time course of pharmacodynamics response are unknown. Cardiac Electrophysiology - The effect of brexanolone on the QT interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, three-period crossover thorough QT study in 30 healthy adult subjects. At 1.9-times the exposure occurring at the highest recommended infusion rate (90 mcg/kg/hour), brexanolone did not prolong the QT interval to a clinically relevant extent. ## Pharmacokinetics - Brexanolone exhibited dose proportional pharmacokinetics over a dosage range of 30 mcg/kg/hour to 270 mcg/kg/hour (three times the maximum recommended dosage). Mean steady state exposure at 60 mcg/kg/hour and 90 mcg/kg/hour was around 52 ng/mL and 79 ng/mL, respectively. Distribution - The volume of distribution of brexanolone was approximately 3 L/kg, suggesting extensive distribution into tissues. Plasma protein binding was greater than 99% and is independent of plasma concentrations. Elimination - The terminal half-life of brexanolone is approximately 9 hours. The total plasma clearance of brexanolone is approximately 1 L/h/kg. Metabolism - Brexanolone is extensively metabolized by non-CYP based pathways via three main routes - keto-reduction (AKRs), glucuronidation (UGTs), and sulfation (SULTs). There are three major circulating metabolites that are pharmacologically inactive and do not contribute to the overall efficacy of brexanolone. Excretion - Following administration of radiolabeled brexanolone, 47% was recovered in feces (primarily as metabolites) and 42% in urine (with less than 1% as unchanged brexanolone). Specific Populations - No clinically significant differences in the pharmacokinetics of brexanolone were observed based on renal impairment (severe) study or hepatic impairment (mild, moderate, severe) study. The effect of end stage renal disease (ESRD, eGFR < 15 mL/minute/1.73 m2) on brexanolone pharmacokinetics is unknown. However, avoid use of brexanolone in patients with ESRD. Drug Interaction Studies - No studies were conducted to evaluate the effects of other drugs on brexanolone. - No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when it was used concomitantly with brexanolone. Betadex Sulfobutyl Ether Sodium Pharmacokinetics - Betadex sulfobutyl ether sodium is a solubilizing agent in brexanolone. In patients with severe renal impairment (eGFR 15-29 mL/minute/1.73 m2), betadex sulfobutyl ether sodium AUCinf increased 5.5-fold and Cmax increased 1.7-fold. Avoid use of brexanolone in patients with ESRD. ## Nonclinical Toxicology Carcinogenesis - Carcinogenicity studies of brexanolone have not been performed. Mutagenesis - Brexanolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay. Impairment of Fertility - Treatment of female and male rats with brexanolone at doses equal to and greater than 30 mg/kg/day, which is associated with 2 times the plasma levels at the maximum recommended human dose (MRHD) of 90 mcg/kg/hour, caused impairment of female and male fertility and reproduction. In female rats, brexanolone was associated with decreased mating and fertility indices, an increase in number of days to mating, prolonged/irregular estrous cycles, an increase in the number of early resorptions, and post implantation loss. Reversal of effects in females was observed following a 28-day recovery period. In male rats, brexanolone was associated with decreased mating and fertility indices, decreased conception rate, lower prostate, seminal vesicle, and epididymis weight, as well as decreased sperm numbers. Impaired female and male fertility and reproduction were not observed at 0.8 times the MRHD. # Clinical Studies - The efficacy of brexanolone in the treatment of postpartum depression (PPD) was demonstrated in two multicenter, randomized, double-blind, placebo-controlled studies (referred to as Studies 1 and 2) in women (18 to 45 years) with PPD who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode (DSM-IV) with onset of symptoms in the third trimester or within 4 weeks of delivery. In these studies, patients received a 60-hour continuous intravenous infusion of brexanolone or placebo and were then followed for 4 weeks. Study 1 (NCT02942004) included patients with severe PPD (Hamilton Depression Rating Scale (HAM-D) score ≥ 26), and Study 2 (NCT02942017) included patients with moderate PPD (HAM-D score of 20 to 25). A titration to the recommended target dosage of 90 mcg/kg/hour was evaluated in both studies (patients received 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for 20 hours, 90 mcg/kg/hour for 28 hours, followed by a taper to 60 mcg/kg/hour for 4 hours and then 30 mcg/kg/hour for 4 hours). A titration to a target dosage of 60 mcg/kg/hour (patients received 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for 52 hours, then 30 mcg/kg/hour for 4 hours) was also evaluated in Study 1. - Demographic and baseline disease characteristics were generally similar across treatment groups in the pooled Studies 1 and 2. Most patients were White (63%) or Black (34%); 18% of patients identified as Hispanic or Latina; the average age of women receiving brexanolone was 28 years. Most patients (76%) had onset of PPD symptoms within 4 weeks after delivery, with the remainder having onset during the third trimester. Baseline oral antidepressant use was reported for 23% of patients. - The primary endpoint was the mean change from baseline in depressive symptoms as measured by the HAM-D total score at the end of the infusion (Hour 60). A pre-specified secondary efficacy endpoint was the mean change from baseline in HAM-D total score at Day 30. In both placebo-controlled studies, titration to a target dose of brexanolone 90 mcg/kg/hour was superior to placebo in improvement of depressive symptoms. In a group of 38 patients in Study 1, a brexanolone titration to a target dose of 60 mcg/kg/hour was also superior to placebo in improvement of depressive symptoms. - Examination of subgroups by race did not suggest differences in response. Time Course of Treatment Response - FIGURE 1 shows the time course of response for the brexanolone 90 mcg/kg/hour-target and 60 mcg/kg/hour-target groups compared to the placebo group for Study 1. # How Supplied - Brexanolone injection is supplied as 100 mg brexanolone in 20 mL (5 mg/mL) single-dose vials containing a sterile, preservative-free, clear, colorless solution. ## Storage - Store the undiluted brexanolone product at 2°C to 8°C (36°F to 46°F). Do not freeze. Store protected from light. - The diluted product in the infusion bag can be used at room temperature for up to 12 hours. If the diluted product is not used immediately after dilution, store under refrigerated conditions for up to 96 hours. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE). Excessive Sedation and Sudden Loss of Consciousness - Patients may experience loss of consciousness or altered state of consciousness during the brexanolone infusion. Advise patients to report signs of excessive sedation that may occur during the infusion. Patients must not be the primary caregiver of dependents and must be accompanied during interactions with their child(red). Zulresso Risk Evaluation and Mitigation Strategy (REMS) - Brexanolone is available only through a restricted program called the Zulresso REMS. - Inform the patient of the following notable requirements: Patients must be enrolled in the Zulresso REMS Program prior to administration. Patients must be monitored during administration of brexanolone and report any signs and symptoms of excessive sedation to a healthcare provider. - Patients must be enrolled in the Zulresso REMS Program prior to administration. - Patients must be monitored during administration of brexanolone and report any signs and symptoms of excessive sedation to a healthcare provider. Potential for Abuse - Advise patients that brexanolone can be abused or lead to dependence. Concomitant Medications - Caution patients that opioids or other CNS depressants, such as benzodiazepines, taken in combination with brexanolone may increase the severity of sedative effects. Suicide Thoughts and Behaviors - Advise patients and caregivers to look for the emergence of suicidal thoughts and behavior and instruct them to report such symptoms to the healthcare provider. Pregnancy - Advise women to notify their healthcare provider if they could possibly be pregnant prior to therapy with brexanolone. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to brexanolone during pregnancy. # Precautions with Alcohol - Concomitant use of alcohol may increase the likelihood or severity of adverse reactions related to sedation. # Brand Names Zulresso # Look-Alike Drug Names There is limited information regarding Brexanolone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Brexanolone
142b2abb3c1778d13f52a483448b8b18f5efda5b	wikidoc	Briakinumab	Briakinumab # Overview Briakinumab (ABT-874) is a human monoclonal antibody being developed by Abbott Laboratories for the treatment of rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. As of 2011 drug development for psoriasis has been discontinued in the U.S. and Europe. Like ustekinumab, the antibody targets the interleukins 12 and 23. # Discovery The candidate drug was discovered by Cambridge Antibody Technology in collaboration with Abbott. # Trials As of November 2009, Phase III clinical trials for plaque psoriasis and a Phase II trial for multiple sclerosis have been completed, and a Phase II trial for Crohn's disease is underway. Briakinumab was compared to etanercept and placebo in several double-blind trials. The Psoriasis Area Severity Index (PASI) was reduced significantly better than under the comparator treatments. 81–82% of patients under briakinumab, 40–56% under etanercept, and 7% under placebo reached PASI reduction of at least 75%. No head-to-head studies against ustekinumab, the other IL-12/23 inhibitor, are available. On January 15, 2011, Abbott announced the withdrawal of its application to the US FDA and European regulators for briakinumab. Following feedback from regulatory authorities indicating the need for further analysis, including the potential for additional studies, Abbott withdrew its applications and was evaluating next steps including possible resubmission at a later date. This compound has never been resubmitted for approval. # Royalties This is the second candidate from a deal with Cambridge Antibody Technology that Abbott have taken to late-stage clinical trials. As a result of the protracted royalty dispute over Humira Abbott agreed to pay CAT a reduced royalty of 4.75% on any future sales of ABT-874, from which CAT will pay a portion to the MRC and other licensors (according to CAT's 1997 agreement with the MRC).	Briakinumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Briakinumab (ABT-874) is a human monoclonal antibody being developed by Abbott Laboratories for the treatment of rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. As of 2011 drug development for psoriasis has been discontinued in the U.S. and Europe.[1] Like ustekinumab, the antibody targets the interleukins 12 and 23.[2] # Discovery The candidate drug was discovered by Cambridge Antibody Technology in collaboration with Abbott.[3][4] # Trials As of November 2009[update], Phase III clinical trials for plaque psoriasis[5][6] and a Phase II trial for multiple sclerosis[7] have been completed, and a Phase II trial for Crohn's disease is underway.[8] Briakinumab was compared to etanercept and placebo in several double-blind trials. The Psoriasis Area Severity Index (PASI) was reduced significantly better than under the comparator treatments. 81–82% of patients under briakinumab, 40–56% under etanercept, and 7% under placebo reached PASI reduction of at least 75%.[9] No head-to-head studies against ustekinumab, the other IL-12/23 inhibitor, are available. On January 15, 2011, Abbott announced the withdrawal of its application to the US FDA and European regulators for briakinumab. Following feedback from regulatory authorities indicating the need for further analysis, including the potential for additional studies, Abbott withdrew its applications and was evaluating next steps including possible resubmission at a later date. This compound has never been resubmitted for approval. # Royalties This is the second candidate from a deal with Cambridge Antibody Technology that Abbott have taken to late-stage clinical trials. As a result of the protracted royalty dispute over Humira Abbott agreed to pay CAT a reduced royalty of 4.75% on any future sales of ABT-874, from which CAT will pay a portion to the MRC and other licensors (according to CAT's 1997 agreement with the MRC).[10]	https://www.wikidoc.org/index.php/Briakinumab
9c9229f919812c5a98c873c6bb54b935d1ccd588	wikidoc	Brifentanil	Brifentanil Brifentanil (A-3331) is an opioid analgesic that is an analogue of fentanyl and was developed in the early 1990s. Brifentanil is most similar to highly potent, short-acting fentanyl analogues such as alfentanil. The effects of brifentanil are very similar to those of alfentanil, with strong but short lasting analgesia and sedation, and particularly notable itching and respiratory depression. Side effects of fentanyl analogues are similar to those of fentanyl, and include itching, nausea and potentially serious respiratory depression which can be life-threatening. The risk of respiratory depression is especially high with potent fentanyl analogues such as alfentanil and brifentanil, and these drugs pose a significant risk of death if used outside of a hospital setting with appropriate artificial breathing apparatus available.	Brifentanil Brifentanil (A-3331) is an opioid analgesic that is an analogue of fentanyl and was developed in the early 1990s.[1] Brifentanil is most similar to highly potent, short-acting fentanyl analogues such as alfentanil. The effects of brifentanil are very similar to those of alfentanil, with strong but short lasting analgesia and sedation, and particularly notable itching and respiratory depression.[2] Side effects of fentanyl analogues are similar to those of fentanyl, and include itching, nausea and potentially serious respiratory depression which can be life-threatening. The risk of respiratory depression is especially high with potent fentanyl analogues such as alfentanil and brifentanil, and these drugs pose a significant risk of death if used outside of a hospital setting with appropriate artificial breathing apparatus available.	https://www.wikidoc.org/index.php/Brifentanil
bf31efe05934779c3c3dc64d878cc56e76f63e97	wikidoc	Brodifacoum	Brodifacoum Brodifacoum is a highly lethal anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide but is also used to control rabbits, possums and other mammalian pests. Brodifacoum, like most anticoagulant poisons, has the advantage that one of its first effects is dehydration, forcing the rodent to move away from human habitation in search of water. As such, there is less chance that homeowners will be forced to deal with decomposing remains inside their building. Dehydrated bodies also dry out more readily, possibly leaving an odorless, mummified carcass. # Toxicology Brodifacoum has a similar mode of action to warfarin. However due to very high potency and long duration of action (elimination half-life of 20 – 130 days), it is characterised as a "second generation" or "superwarfarin" anticoagulant. Brodifacoum inhibits the enzyme Vitamin K epoxide reductase. This enzyme is needed for the reconstitution of the vitamin K in its cycle from vitamin K-epoxide, and so brodifacoum steadily decreases the level of active vitamin K in the blood. Vitamin K is required for the synthesis of important substances including prothrombin, which is involved in blood clotting. This disruption becomes increasingly severe until the blood effectively loses any ability to clot. In addition, brodifacoum (as with other anticoagulants in toxic doses) increases permeability of blood capillaries; the blood plasma and blood itself begins to leak from the smallest blood vessels. A poisoned animal will suffer progressively worsening internal bleeding, leading to shock, loss of consciousness, and eventually death. Brodifacoum is highly lethal to mammals and birds, and extremely lethal to fish. It is a highly cumulative poison, due to its high lipophilicity and extremely slow elimination. Following are acute LD50 values for various animals (mammals): - rats (oral) 0.27—0.30 mg/kg b.w. - mice (oral) 0.40 mg/kg b.w. - rabbits (oral) 0.30 mg/kg b.w. - guinea-pigs (oral) 0.28 mg/kg b.w. - cats (oral) 0.25 mg/kg b.w. - dogs (oral) 0.25 mg/kg b.w. LD50 values for various birds varies from about 1 mg/kg b.w. — 20 mg/kg b.w.. LC50 (concentration prone of killing 50% of animals exposed to it) for fish: - trout (96 hours exposure) 0.04 ppm Given these extremely high toxicities in various mammals, brodifacoum is classified as "extremely toxic" (LD50 < 1.0 mg/kg b.w.) and "very toxic" (T+; LD50 < 25 mg/kg b.w.), respectively. Because of its persistency, cumulative potential and high toxicities for various wildlife species, it is also considered an environmental pollutant (N; noxious to the environment). The readiness of brodifacoum to penetrate intact skin should be noted, and brodifacoum and commercial preparations containing it should be handled with respective care and precaution because of its skin resorptivity. The estimated average fatal dose for an adult man (60 kg b.w.) is about 15 mg, without treatment. However, due to low bait concentrations (usually 10 — 50 mg/kg bait, i.e. 0.001 — 0.005%) and slow onset of symptoms, and the existence of a highly effective antidote (appropriately dosed vitamin K1), brodifacoum is considered to be of relatively low hazard to humans. # Brand names Brodifacoum is marketed under a large variety of trade names, including d-Con, Finale, Fologorat, Havoc, Jaguar, Klerat, Matikus, Mouser, Pestoff, Ratak+, Rodend, Talon, Volak and Volid. # Treatment The primary antidote to brodifacoum poisoning is immediate administration of vitamin K1 (initially slow intravenous injections of 10-25 mg repeated all 3–6 hours until normalisation of the prothrombin time; then 10 mg orally four times daily as a "maintenance dose"). It is an extremely effective antidote, provided the poisoning is caught before too much damage has been done to the victim's circulatory system. As high doses of brodifacoum can affect the body for many months, the antidote must be administered regularly for a long period with frequent monitoring of the prothrombin time. If unabsorbed poison is still in the digestive system, gastric lavage followed by administration of activated charcoal may be required. Further treatments to be considered include infusion of blood or plasma to counteract hypovolemic shock; and in severe cases, infusion of blood clotting factor concentrate. Administration of vitamin C is also recommended (100 mg three times daily). Another potential treatment is phenobarbital, which is believed to accelerate the metabolism of some anticoagulants via enzyme induction. # Poisoning case reports There have been at least ten case reports of brodifacoum intoxication in the medical literature. In one report, a woman deliberately consumed over 1.5 kilograms of rat bait, constituting about 75 mg brodifacoum, but made a full recovery after receiving conventional medical treatment. In another report, a 17-year-old boy presented to the hospital with a severe bleeding disorder. It was discovered that he habitually smoked a mixture of brodifacoum and marijuana. Despite treatment with vitamin K, the bleeding disorder persisted for several months. He eventually recovered. # Notes - ↑ Eason, C.T. and Wickstrom, M. Vertebrate pesticide toxicology manual, New Zealand Department of Conservation - ↑ #search=%22LC50%2Bbrodifacoum%22 - ↑ Lipton, R.A. & Klass, E.M. (1984) Human ingestion of a 'superwarfarin' rodenticide resulting in a prolonged anticoagulant effect. JAMA 252:3004-3005. - ↑ La Rosa, F, Clarke, S. & Lefkowitz, J. B. (1997) Brodifacoum intoxication with marijuana smoking. Archives of Pathology & Laboratory Medicine 121:67-69. New England Journal of Medicine, vol 356, no. 2, Jan. 11, 2007 Case Records of the Massachusetts General Hospital (a near fatal case of brodifacoum poisoning). # Further reading - Tasheva, M. (1995). Environmental Health Criteria 175: Anticoagulant rodenticides. World Health Organisation: Geneva.	Brodifacoum Brodifacoum is a highly lethal anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide but is also used to control rabbits, possums and other mammalian pests[1]. Brodifacoum, like most anticoagulant poisons, has the advantage that one of its first effects is dehydration, forcing the rodent to move away from human habitation in search of water. As such, there is less chance that homeowners will be forced to deal with decomposing remains inside their building. Dehydrated bodies also dry out more readily, possibly leaving an odorless, mummified carcass. # Toxicology Brodifacoum has a similar mode of action to warfarin. However due to very high potency and long duration of action (elimination half-life of 20 – 130 days), it is characterised as a "second generation" or "superwarfarin" anticoagulant.[2] Brodifacoum inhibits the enzyme Vitamin K epoxide reductase. This enzyme is needed for the reconstitution of the vitamin K in its cycle from vitamin K-epoxide, and so brodifacoum steadily decreases the level of active vitamin K in the blood. Vitamin K is required for the synthesis of important substances including prothrombin, which is involved in blood clotting. This disruption becomes increasingly severe until the blood effectively loses any ability to clot. In addition, brodifacoum (as with other anticoagulants in toxic doses) increases permeability of blood capillaries; the blood plasma and blood itself begins to leak from the smallest blood vessels. A poisoned animal will suffer progressively worsening internal bleeding, leading to shock, loss of consciousness, and eventually death. Brodifacoum is highly lethal to mammals and birds, and extremely lethal to fish. It is a highly cumulative poison, due to its high lipophilicity and extremely slow elimination. Following are acute LD50 values for various animals (mammals)[3]: - rats (oral) 0.27—0.30 mg/kg b.w. - mice (oral) 0.40 mg/kg b.w. - rabbits (oral) 0.30 mg/kg b.w. - guinea-pigs (oral) 0.28 mg/kg b.w. - cats (oral) 0.25 mg/kg b.w. - dogs (oral) 0.25 mg/kg b.w. LD50 values for various birds varies from about 1 mg/kg b.w. — 20 mg/kg b.w.[4]. LC50 (concentration prone of killing 50% of animals exposed to it) for fish: - trout (96 hours exposure) 0.04 ppm[5] Given these extremely high toxicities in various mammals, brodifacoum is classified as "extremely toxic" (LD50 < 1.0 mg/kg b.w.) and "very toxic" (T+; LD50 < 25 mg/kg b.w.), respectively. Because of its persistency, cumulative potential and high toxicities for various wildlife species, it is also considered an environmental pollutant (N; noxious to the environment). The readiness of brodifacoum to penetrate intact skin should be noted, and brodifacoum and commercial preparations containing it should be handled with respective care and precaution because of its skin resorptivity. The estimated average fatal dose for an adult man (60 kg b.w.) is about 15 mg, without treatment[6]. However, due to low bait concentrations (usually 10 — 50 mg/kg bait, i.e. 0.001 — 0.005%) and slow onset of symptoms, and the existence of a highly effective antidote (appropriately dosed vitamin K1), brodifacoum is considered to be of relatively low hazard to humans. # Brand names Brodifacoum is marketed under a large variety of trade names, including d-Con, Finale, Fologorat, Havoc, Jaguar, Klerat, Matikus, Mouser, Pestoff, Ratak+, Rodend, Talon, Volak and Volid. # Treatment The primary antidote to brodifacoum poisoning is immediate administration of vitamin K1 (initially slow intravenous injections of 10-25 mg repeated all 3–6 hours until normalisation of the prothrombin time; then 10 mg orally four times daily as a "maintenance dose"). It is an extremely effective antidote, provided the poisoning is caught before too much damage has been done to the victim's circulatory system. As high doses of brodifacoum can affect the body for many months, the antidote must be administered regularly for a long period with frequent monitoring of the prothrombin time. If unabsorbed poison is still in the digestive system, gastric lavage followed by administration of activated charcoal may be required. Further treatments to be considered include infusion of blood or plasma to counteract hypovolemic shock; and in severe cases, infusion of blood clotting factor concentrate. Administration of vitamin C is also recommended (100 mg three times daily)[7]. Another potential treatment is phenobarbital, which is believed to accelerate the metabolism of some anticoagulants via enzyme induction. # Poisoning case reports There have been at least ten case reports of brodifacoum intoxication in the medical literature. In one report[8], a woman deliberately consumed over 1.5 kilograms of rat bait, constituting about 75 mg brodifacoum, but made a full recovery after receiving conventional medical treatment. In another report[9], a 17-year-old boy presented to the hospital with a severe bleeding disorder. It was discovered that he habitually smoked a mixture of brodifacoum and marijuana. Despite treatment with vitamin K, the bleeding disorder persisted for several months. He eventually recovered. # Notes - ↑ Eason, C.T. and Wickstrom, M. Vertebrate pesticide toxicology manual, New Zealand Department of Conservation - ↑ http://www.inchem.org/documents/hsg/hsg/hsg093.htm - ↑ http://www.inchem.org/documents/pds/pds/pest57_e.htm - ↑ http://www.inchem.org/documents/hsg/hsg/hsg093.htm - ↑ http://www.wil-kil.com/public/2005-06_labels-msds/WeatherBlok%20XT%20M.pdf#search=%22LC50%2Bbrodifacoum%22 - ↑ http://www.inchem.org/documents/hsg/hsg/hsg093.htm - ↑ http://www.inchem.org/documents/pds/pds/pest57_e.htm - ↑ Lipton, R.A. & Klass, E.M. (1984) Human ingestion of a 'superwarfarin' rodenticide resulting in a prolonged anticoagulant effect. JAMA 252:3004-3005. - ↑ La Rosa, F, Clarke, S. & Lefkowitz, J. B. (1997) Brodifacoum intoxication with marijuana smoking. Archives of Pathology & Laboratory Medicine 121:67-69. New England Journal of Medicine, vol 356, no. 2, Jan. 11, 2007 Case Records of the Massachusetts General Hospital (a near fatal case of brodifacoum poisoning).[1] # Further reading - Tasheva, M. (1995). Environmental Health Criteria 175: Anticoagulant rodenticides. World Health Organisation: Geneva. # External links de:Brodifacoum	https://www.wikidoc.org/index.php/Brodifacoum
a7512de207453bb5e78f897040fe19e51943d8a3	wikidoc	Bromoethane	Bromoethane # Overview Bromoethane, also known as ethyl bromide is a chemical compound of the haloalkanes group. It is abbreviated by chemists as EtBr. This volatile compound has an ether-like odour. # Synthesis The preparation of EtBr stands as a model for the synthesis of alkyl bromides in general. It is usually prepared by the addition of HBr to ethylene: Ethyl bromide is inexpensive and would rarely be prepared in the laboratory. Convenient laboratory syntheses include the action of phosphorus tribromide or thionyl bromide on ethanol. EtBr forms when ethanol is treated with HBr or hydrobromic acid, although this reaction also affords diethyl ether. # Uses In organic synthesis, EtBr is the synthetic equivalent of the ethyl carbocation (Et+) synthon. In reality, such a cation is not actually formed. For example, carboxylates salts are converted to ethyl esters, carbanions to ethylated derivatives, thiourea into ethylisothiouronium salts, and amines into ethylamines. Being a liquid at room temperature but still very volatile, EtBr is an inexpensive reagent for the preparation of Grignard reagents, which traditionally were used as strong base. Thus EtMgBr deprotonates alkynes: This application has been supplanted by the wide availability of organolithium reagents. # Safety Halocarbons in general are potentially dangerous alkylating agents. Bromides are more superior alkylating agents than chlorides, thus exposure to EtBr should be minimized. EtBr is classified by the State of California as carcinogenic and a reproductive toxin.	Bromoethane Template:Chembox new # Overview Bromoethane, also known as ethyl bromide is a chemical compound of the haloalkanes group. It is abbreviated by chemists as EtBr. This volatile compound has an ether-like odour. # Synthesis The preparation of EtBr stands as a model for the synthesis of alkyl bromides in general. It is usually prepared by the addition of HBr to ethylene: Ethyl bromide is inexpensive and would rarely be prepared in the laboratory. Convenient laboratory syntheses include the action of phosphorus tribromide or thionyl bromide on ethanol. EtBr forms when ethanol is treated with HBr or hydrobromic acid, although this reaction also affords diethyl ether. # Uses In organic synthesis, EtBr is the synthetic equivalent of the ethyl carbocation (Et+) synthon. In reality, such a cation is not actually formed. For example, carboxylates salts are converted to ethyl esters,[1] carbanions to ethylated derivatives, thiourea into ethylisothiouronium salts,[2] and amines into ethylamines.[3] Being a liquid at room temperature but still very volatile, EtBr is an inexpensive reagent for the preparation of Grignard reagents, which traditionally were used as strong base. Thus EtMgBr deprotonates alkynes:[4][5][6] This application has been supplanted by the wide availability of organolithium reagents. # Safety Halocarbons in general are potentially dangerous alkylating agents. Bromides are more superior alkylating agents than chlorides, thus exposure to EtBr should be minimized. EtBr is classified by the State of California as carcinogenic and a reproductive toxin.	https://www.wikidoc.org/index.php/Bromoethane
fe0e02b774fd8d99b0665ca76abeba1007875f0b	wikidoc	Brown tumor	Brown tumor # Overview Brown tumors are tumors of bone that arise in settings of excess osteoclast activity, such as hyperparathyroidism, and consist of fibrous tissue, woven bone and supporting vasculature, but no matrix. They are radiolucent on x-ray. The osteoclasts consume the trabecular bone that osteoblasts lay down and this front of reparative bone deposition followed by addition resorption can expand beyond the usual contour of the bone, involving the periosteum and causing bone pain. The characteristic brown coloration results from hemorrhage into the ostelytic cysts. Brown tumors represent a reparative cellular process rather than a neoplastic process. In chronic renal disease, continual, excessive urinary calcium excretion can lower the serum calcium level and lead to a rise in parathonmone secretion so that skeletal calcium can be mobilized to maintain normal serum calcium levels. This mobilization occurs through rapid osteoclastic turnover of bone, a direct effect of parathormone on bone. In localized regions where bone loss is particularly rapid, hemorrhage, reparative granulation tissue, and active, vascular, proliferating fibrous tissue may replace the normal marrow contents, resulting in a brown tumor. Hemosidenin imparts the brown color. Brown tumors have a slightly greater frequency in primary hyperparathyroidism than in secondary hyperparathyroidism (3% vs 2%). However, secondary hyperparathyroidism is much more common than primary hypenparathyroidism so that most brown tumors are associated with secondary hyperparathyroidism. # Causes - Hyperparathyroidism # Diagnosis The following are the imaging findings ## X-ray - Well-defined, purely lytic lesions that provoke little reactive bone. The cortex may be thinned and expanded, but will not be penetrated. ## CT - Attenuation values on CT will be in the range of blood and fibrous tissue. ## Angiography - Hypervascular. ## Bone scan - Intensely uptake. Patient #1: Hip pain in a patient with hyperparathyroidism Patient #1: Primary hyperparathyroidism	Brown tumor Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Brown tumors are tumors of bone that arise in settings of excess osteoclast activity, such as hyperparathyroidism[2], and consist of fibrous tissue, woven bone and supporting vasculature, but no matrix. They are radiolucent on x-ray. The osteoclasts consume the trabecular bone that osteoblasts lay down and this front of reparative bone deposition followed by addition resorption can expand beyond the usual contour of the bone, involving the periosteum and causing bone pain. The characteristic brown coloration results from hemorrhage into the ostelytic cysts. Brown tumors represent a reparative cellular process rather than a neoplastic process. In chronic renal disease, continual, excessive urinary calcium excretion can lower the serum calcium level and lead to a rise in parathonmone secretion so that skeletal calcium can be mobilized to maintain normal serum calcium levels. This mobilization occurs through rapid osteoclastic turnover of bone, a direct effect of parathormone on bone. In localized regions where bone loss is particularly rapid, hemorrhage, reparative granulation tissue, and active, vascular, proliferating fibrous tissue may replace the normal marrow contents, resulting in a brown tumor. Hemosidenin imparts the brown color. Brown tumors have a slightly greater frequency in primary hyperparathyroidism than in secondary hyperparathyroidism (3% vs 2%). However, secondary hyperparathyroidism is much more common than primary hypenparathyroidism so that most brown tumors are associated with secondary hyperparathyroidism. # Causes - Hyperparathyroidism # Diagnosis The following are the imaging findings ## X-ray - Well-defined, purely lytic lesions that provoke little reactive bone. The cortex may be thinned and expanded, but will not be penetrated. ## CT - Attenuation values on CT will be in the range of blood and fibrous tissue. ## Angiography - Hypervascular. ## Bone scan - Intensely uptake. Patient #1: Hip pain in a patient with hyperparathyroidism - - - - Patient #1: Primary hyperparathyroidism -	https://www.wikidoc.org/index.php/Brown_tumor
dbc71e0fd2f5ea1eaf791b84eb70438064b26131	wikidoc	Bucladesine	Bucladesine # Overview Bucladesine is a cyclic nucleotide derivative which mimics the action of endogenous cAMP and is a phosphodiesterase inhibitor. Bucladesine is a cell permeable cAMP analog. The compound is used in a wide variety of research applications because it mimics cAMP and can induce normal physiological responses when added to cells in experimental conditions. cAMP is only able to elicit minimal responses in these situations. The neurite outgrowth instigated by bucladesine in cell cultures has been shown to be enhanced by nardosinone.	Bucladesine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Bucladesine is a cyclic nucleotide derivative which mimics the action of endogenous cAMP and is a phosphodiesterase inhibitor. Bucladesine is a cell permeable cAMP analog. The compound is used in a wide variety of research applications because it mimics cAMP and can induce normal physiological responses when added to cells in experimental conditions. cAMP is only able to elicit minimal responses in these situations. The neurite outgrowth instigated by bucladesine in cell cultures has been shown to be enhanced by nardosinone. Template:Phosphodiesterase inhibitors Template:Cardiac stimulants excluding cardiac glycosides	https://www.wikidoc.org/index.php/Bucladesine
a83393741454aff21900b369a564830330f25c89	wikidoc	Bupivacaine	Bupivacaine # 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 Bupivacaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of administration of analgesic, local, administration of analgesic, regional, anesthesia - dental procedure, anesthesia for procedures on eye, local anesthesia, regional anesthesia. Common adverse reactions include cardiovascular: bradyarrhythmia, heart block, ventricular arrhythmia immunologic: bacterial meningitis, septic, immune hypersensitivity reaction (rare ), musculoskeletal: chondrolysis of articular cartilage, neurologic: central nervous system depression, central nervous system stimulation, cranial nerve disorder, paraplegia, seizure (0.1% ), total spinal nerve blockade following local anesthetic injection, respiratory: respiratory arrest. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Administration of analgesic, Local: intrapleural, 10 to 30 mL bolus of 0.25%, 0.375%, or 0.5% every 4 to 8 hours - Administration of analgesic, Local: intrapleural, continuous infusion 0.375% bupivacaine with epinephrine at 6 mL/hr after 20 mL loading dose - Administration of analgesic, Regional: epidural, continuous infusion, 6.25 to 18.75 mg/hr as a 0.0625% to 0.125% solution - Anesthesia - Dental procedure: 1.8 to 3.6 mL of 0.5% solution (9 to 18 mg) with epinephrine; a second dose (9 mg) may be administered; MAX total dose 90 mg - Anesthesia for procedures on eye: complete motor blockade, 2 to 4 mL (15 to 30 mg) of 0.75% solution - Local anesthesia: dosage varies with anesthetic procedure, area to be anesthetized, vascularity of the tissues, number of neuronal segments to be blocked, depth of anesthesia and degree and muscle relaxation required, duration of anesthesia desired, individual tolerance, and physical condition of the patient - Local anesthesia: infiltration, 0.25% solution up to max doses (max 225 mg with epinephrine or 175 mg without epinephrine) - Local anesthesia: sacral epidural block, moderate to complete blockade, 15 to 30 mL of 0.5% solution (75 to 150 mg) OR 0.25% solution (37.5 to 75 mg), repeated once every 3 h as needed - Regional anesthesia: dosage varies with anesthetic procedure, area to be anesthetized, vascularity of the tissues, number of neuronal segments to be blocked, depth of anesthesia and degree and muscle relaxation required, duration of anesthesia desired, individual tolerance, and physical condition of the patient - Regional anesthesia: epidural, partial to moderate motor blockade, 10 to 20 mL (25 to -50 mg) of a 0.25% solution; moderate to complete motor blockade, 10 to 20 mL (50 to 100 mg) as a 0.5% solution; complete motor blockade, 10 to 20 mL (75 to 150 mg) as a 0.75% solution; repeat once every 3 hours as needed - Regional anesthesia: (obstetrical) hyperbaric spinal (bupivacaine in dextrose formulation only), normal vaginal delivery, 0.8 mL (6 mg) bupivacaine in dextrose as 0.75% solution; cesarean section, 1 to 1.4 mL (7.5 to 10.5 mg) bupivacaine in dextrose as 0.75% solution - Regional anesthesia: hyperbaric spinal (bupivacaine in dextrose formulation only), lower extremity and perineal procedures, 1 mL (7.5 mg) bupivacaine in dextrose as 0.75% solution; lower abdominal procedures, 1.6 mL (12 mg) bupivacaine in dextrose as 0.75% solution; upper abdominal surgery, 2 mL (15 mg) bupivacaine in dextrose, in horizontal position - Regional anesthesia: peripheral nerve block, moderate to complete motor blockade, 5 to 37.5 mL (25 to 175 mg) of 0.5% solution OR 5 to 70 mL (12.5 to 175 mg) of 0.25% solution, repeat every 3 hours if necessary - Regional anesthesia: sympathetic nerve block, 20 to 50 mL (50 to 125 mg) of 0.25% solution, repeat once every 3 hours as needed ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Pain ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Bupivacaine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Administration in children younger than 12 years is not recommended - Bupivacaine spinal with dextrose not recommended in children younger than 18 years - Administration of analgesic, Local: intrapleural, continuous infusion 0.25% bupivacaine with epinephrine at 0.5 mL/kg/hr. - Administration of analgesic, Regional: (body weight 10 kg or less) caudal, single dose 1 to 1.25 mg/kg as a 0.125% or 0.25% solution - Administration of analgesic, Regional: (body weight 10 kg or less) caudal, continuous infusion 0.1 to 0.2 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution; max 0.2 mg/kg/hr - Administration of analgesic, Regional: (body weight 10 kg or less) caudal or epidural, single dose 1 to 1.25 mg/kg as a 0.125% or 0.25% solution - Administration of analgesic, Regional: (body weight 10 kg or less) caudal or epidural, continuous infusion 0.1 to 0.2 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution; max 0.2 mg/kg/hr - Administration of analgesic, Regional: (body weight greater than 10 kg) caudal, single dose 1 to 2.5 mg/kg as a 0.125% or 0.25% solution - Administration of analgesic, Regional: (body weight greater than 10 kg) caudal, continuous infusion 0.2 to 0.4 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution, max 0.4 mg/kg/hr - Anesthesia - Dental procedure: (12 years or older) 1.8 to 3.6 mL of 0.5% solution (9 to 18 mg) with epinephrine; a second dose (9 mg) may be administered; max total dose 90 mg - Anesthesia for procedures on eye: (12 years or older) complete motor blockade, 2 to 4 mL (15 to 30 mg) of 0.75% solution - Local anesthesia: infiltration, 0.5 to 2.5 mg/kg as a 0.25% or 0.5% solution; MAX 1 mL/kg of 0.25% solution, 0.5 mL/kg of 0.5% solution - Local anesthesia: sacral epidural block, (body weight greater than 10 kg) single dose 1 to 2.5 mg/kg as a 0.125% or 0.25% solution - Local anesthesia: sacral epidural block, (body weight greater than 10 kg) continuous infusion 0.2 to 0.4 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution, max 0.4 mg/kg/hr - Regional anesthesia: epidural, (body weight greater than 10 kg) single dose 1 to 2.5 mg/kg as a 0.125% or 0.25% solution - Regional anesthesia: epidural, (body weight greater than 10 kg) continuous infusion 0.2 to 0.4 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution, MAX 0.4 mg/kg/hr - Regional anesthesia: hyperbaric spinal (bupivacaine in dextrose formulation only), 0.3 to 0.6 mg/kg bupivacaine in dextrose as a 0.75% solution - Regional anesthesia: peripheral nerve block, 0.3 to 2.5 mg/kg as a 0.25% or 0.5% solution; max 1 mL/kg of 0.25% solution, 0.5 mL/kg of 0.5% solution ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Bupivacaine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Bupivacaine in pediatric patients. # Contraindications - Bupivacaine Spinal is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type. - The following conditions preclude the use of spinal anesthesia: - Severe hemorrhage, severe hypotension or shock and arrhythmias, such as complete heart block, which severely restrict cardiac output. - Local infection at the site of proposed lumbar puncture. - Septicemia. # Warnings - Local anesthetics should only be employed by clinicians who are well versed in diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. (see also adverse reactions and precautions.) delay in proper management of dose-related toxicity, underventilation from any cause and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death. - Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. - Spinal anesthetics should not be injected during uterine contractions, because spinal fluid current may carry the drug further cephalad than desired. - A free flow of cerebrospinal fluid during the performance of spinal anesthesia is indicative of entry into the subarachnoid space. However, aspiration should be performed before the anesthetic solution is injected to confirm entry into the subarachnoid space and to avoid intravascular injection. - Bupivacaine solutions containing epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of Bupivacaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. - Until further experience is gained in patients younger than 18 years, administration of Bupivacaine in this age group is not recommended. - Mixing or the prior or intercurrent use of any other local anesthetic with Bupivacaine cannot be recommended because of insufficient data on the clinical use of such mixtures. # Adverse Reactions ## Clinical Trials Experience - Reactions to bupivacaine are characteristic of those associated with other amide-type local anesthetics. - The most commonly encountered acute adverse experiences which demand immediate countermeasures following the administration of spinal anesthesia are hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia. These may lead to cardiac arrest if untreated. In addition, dose-related convulsions and cardiovascular collapse may result from diminished tolerance, rapid absorption from the injection site, or from unintentional intravascular injection of a local anesthetic solution. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. - Respiratory paralysis or underventilation may be noted as a result of upward extension of the level of spinal anesthesia and may lead to secondary hypoxic cardiac arrest if untreated. Preanesthetic medication, intraoperative analgesics and sedatives, as well as surgical manipulation, may contribute to underventilation. This will usually be noted within minutes of the injection of spinal anesthetic solution, but because of differing maximal onset times, differing intercurrent drug usage and differing surgical manipulation, it may occur at any time during surgery or the immediate recovery period. - Hypotension due to loss of sympathetic tone is a commonly encountered extension of the clinical pharmacology of spinal anesthesia. This is more commonly observed in elderly patients, particularly those with hypertension, and patients with shrunken blood volume, shrunken interstitial fluid volume, cephalad spread of the local anesthetic, and/or mechanical obstruction of venous return. Nausea and vomiting are frequently associated with hypotensive episodes following the administration of spinal anesthesia. High doses, or inadvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, bradycardia, heart block, ventricular arrhythmias, and, possibly, cardiac arrest. (See Warnings, Precautions, and Overdosage sections.) - Respiratory paralysis or underventilation secondary to cephalad spread of the level of spinal anesthesia (see Respiratory System) and hypotension for the same reason (see Cardiovascular System) are the two most commonly encountered central nervous system-related adverse observations which demand immediate countermeasures. - High doses or inadvertent intravascular injection may lead to high plasma levels and related central nervous system toxicity characterized by excitement and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. - The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. - Neurologic effects following spinal anesthesia may include loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness and paralysis of the lower extremities, and loss of sphincter control all of which may have slow, incomplete, or no recovery; hypotension, high or total spinal block; urinary retention; headache; backache; septic meningitis, meningismus; arachnoiditis; slowing of labor; increased incidence of forceps delivery; shivering; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid; and fecal and urinary incontinence. - Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and, possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. - Nausea and vomiting may occur during spinal anesthesia. ## Postmarketing Experience There is limited information regarding Bupivacaine Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Bupivacaine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies in pregnant women. Bupivacaine Spinal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of Bupivacaine Spinal at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.) - Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are approximately 30-times the daily maximum recommended human dose (MRHD) of 12 mg/day on a mg dose/m2 body surface area (BSA) basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level being approximately 8-times the MRHD on a BSA basis. - In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg, decreased pup survival was observed at the high dose. The high dose is approximately 30-times the daily MRHD of 12 mg/day on a BSA basis. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bupivacaine in women who are pregnant. ### Labor and Delivery - Spinal anesthesia has a recognized use during labor and delivery. Bupivacaine hydrochloride, when administered properly, via the epidural route in doses 10 to 12 times the amount used in spinal anesthesia has been used for obstetrical analgesia and anesthesia without evidence of adverse effects on the fetus. - Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. - It is extremely important to avoid aortocaval compression by the gravid uterus during administrations of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left. - Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. - The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine. - There have been reports of cardiac arrest during use of Bupivacaine 0.75% solution for epidural anesthesia in obstetrical patients. The package insert for Bupivacaine hydrochloride for epidural, nerve block, etc., has a more complete discussion of preparation for, and management of, this problem. These cases are compatible with systemic toxicity following unintended intravascular injection of the much larger doses recommended for epidural anesthesia and have not occurred within the dose range of bupivacaine hydrochloride 0.75% recommended for spinal anesthesia in obstetrics. The 0.75% concentration of Bupivacaine is therefore not recommended for obstetrical epidural anesthesia. Bupivacaine Spinal (bupivacaine hydrochloride in dextrose injection) is recommended for spinal anesthesia in obstetrics. ### Nursing Mothers - Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue nursing or not administer bupivacaine, taking into account the importance of the drug to the mother. ### Pediatric Use - Until further experience is gained in patients younger than 18 years, administration of Bupivacaine Spinal in this age group is not recommended. ### Geriatic Use - Patients over 65 years, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing spinal anesthesia with Bupivacaine Spinal. (See Precautions, General And Adverse Reactions, Cardiovascular System.) - Elderly patients may require lower doses of Bupivacaine Spinal. (See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION.) - In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. (See Clinical Pharmacology, Pharmacokinetics.) - This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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. (See Clinical Pharmacology, Pharmacokinetics.) ### Gender There is no FDA guidance on the use of Bupivacaine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bupivacaine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bupivacaine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Bupivacaine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bupivacaine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bupivacaine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Bupivacaine Administration in the drug label. ### Monitoring There is limited information regarding Bupivacaine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Bupivacaine and IV administrations. # Overdosage - Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use or to underventilation (and perhaps apnea) secondary to upward extension of spinal anesthesia. Hypotension is commonly encountered during the conduct of spinal anesthesia due to relaxation of sympathetic tone, and sometimes, contributory mechanical obstruction of venous return. - The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. - The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to a high or total spinal, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred. - If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). - Hypotension due to sympathetic relaxation may be managed by giving intravenous fluids (such as isotonic saline or lactated Ringer’s solution), in an attempt to relieve mechanical obstruction of venous return, or by using vasopressors (such as ephedrine which increases the force of myocardial contractions) and, if indicated, by giving plasma expanders or whole blood. - Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated. - Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. - If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to a high or total spinal may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary. Recovery has been reported after prolonged resuscitative efforts. - The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. - The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg to 8 mg/kg and 38 mg/kg to 54 mg/kg respectively. # Pharmacology ## Mechanism of Action - Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: - Pain, - Temperature, - Touch, - Proprioception, - Skeletal muscle tone. - Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended direct intravascular injection of bupivacaine. Therefore, when epidural anesthesia with bupivacaine is considered, incremental dosing is necessary. - Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage. ## Structure - Bupivacaine hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula: - BupivacaineTM Spinal is available in sterile hyperbaric solution for subarachnoid injection (spinal block). - Bupivacaine hydrochloride is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. - Each mL of Bupivacaine Spinal contains 7.5 mg bupivacaine hydrochloride (anhydrous) and 82.5 mg dextrose (anhydrous). The pH of this solution is adjusted to between 4.0 and 6.5 with sodium hydroxide or hydrochloric acid. - The specific gravity of Bupivacaine Spinal is between 1.030 and 1.035 at 25°C and 1.03 at 37°C. - Bupivacaine Spinal does not contain any preservatives. ## Pharmacodynamics There is limited information regarding Bupivacaine Pharmacodynamics in the drug label. ## Pharmacokinetics - The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma concentration of Bupivacaine, permitting the use of moderately larger total doses and sometimes prolonging the duration of action. - The onset of action with Bupivacaine is rapid and anesthesia is long lasting. The duration of anesthesia is significantly longer with Bupivacaine than with any other commonly used local anesthetic. It has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesics is reduced. - The onset of sensory blockade following spinal block with Bupivacaine Spinal is very rapid (within one minute); maximum motor blockade and maximum dermatome level are achieved within 15 minutes in most cases. Duration of sensory blockade (time to return of complete sensation in the operative site or regression of two dermatomes) following a 12 mg dose averages 2 hours with or without 0.2 mg epinephrine. The time to return of complete motor ability with 12 mg Bupivacaine Spinal averages 3 1/2 hours without the addition of epinephrine and 4 1/2 hours if 0.2 mg epinephrine is added. When compared to equal milligram doses of hyperbaric tetracaine, the duration of sensory blockade was the same but the time to complete motor recovery was significantly longer for tetracaine. Addition of 0.2 mg epinephrine significantly prolongs the motor blockade and time to first postoperative narcotic with Bupivacaine Spinal. - Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by: - The degree of plasma protein binding, - The degree of ionization, and - The degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. - Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. - Pharmacokinetic studies on the plasma profiles of Bupivacaine after direct intravenous injection suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized. - Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of Bupivacaine in adults is 2.7 hours and in neonates 8.1 hours. In clinical studies, elderly patients exhibited a greater spread and higher maximal level of analgesia than younger patients. Elderly patients also reached the maximal level of analgesia more rapidly than younger patients, and exhibited a faster onset of motor blockade. The total plasma clearance was decreased and the terminal half-life was lengthened in these patients. - Amide-type local anesthetics such as Bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecolylxylidine is the major metabolite of Bupivacaine. - The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine. - When administered in recommended doses and concentrations, Bupivacaine does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia. ## Nonclinical Toxicology There is limited information regarding Bupivacaine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Bupivacaine Clinical Studies in the drug label. # How Supplied - Single-dose ampuls of 2 mL (15 mg bupivacaine hydrochloride with 165 mg dextrose), is supplied as follows: ## Storage - Store at 20 to 25°C (68 to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of spinal anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the Bupivacaine Spinal package insert. # Precautions with Alcohol Alcohol-Bupivacaine 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 Bupivacaine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Bupivacaine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Bupivacaine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, 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 Bupivacaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of administration of analgesic, local, administration of analgesic, regional, anesthesia - dental procedure, anesthesia for procedures on eye, local anesthesia, regional anesthesia. Common adverse reactions include cardiovascular: bradyarrhythmia, heart block, ventricular arrhythmia immunologic: bacterial meningitis, septic, immune hypersensitivity reaction (rare ), musculoskeletal: chondrolysis of articular cartilage, neurologic: central nervous system depression, central nervous system stimulation, cranial nerve disorder, paraplegia, seizure (0.1% ), total spinal nerve blockade following local anesthetic injection, respiratory: respiratory arrest. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Administration of analgesic, Local: intrapleural, 10 to 30 mL bolus of 0.25%, 0.375%, or 0.5% every 4 to 8 hours - Administration of analgesic, Local: intrapleural, continuous infusion 0.375% bupivacaine with epinephrine at 6 mL/hr after 20 mL loading dose - Administration of analgesic, Regional: epidural, continuous infusion, 6.25 to 18.75 mg/hr as a 0.0625% to 0.125% solution - Anesthesia - Dental procedure: 1.8 to 3.6 mL of 0.5% solution (9 to 18 mg) with epinephrine; a second dose (9 mg) may be administered; MAX total dose 90 mg - Anesthesia for procedures on eye: complete motor blockade, 2 to 4 mL (15 to 30 mg) of 0.75% solution - Local anesthesia: dosage varies with anesthetic procedure, area to be anesthetized, vascularity of the tissues, number of neuronal segments to be blocked, depth of anesthesia and degree and muscle relaxation required, duration of anesthesia desired, individual tolerance, and physical condition of the patient - Local anesthesia: infiltration, 0.25% solution up to max doses (max 225 mg with epinephrine or 175 mg without epinephrine) - Local anesthesia: sacral epidural block, moderate to complete blockade, 15 to 30 mL of 0.5% solution (75 to 150 mg) OR 0.25% solution (37.5 to 75 mg), repeated once every 3 h as needed - Regional anesthesia: dosage varies with anesthetic procedure, area to be anesthetized, vascularity of the tissues, number of neuronal segments to be blocked, depth of anesthesia and degree and muscle relaxation required, duration of anesthesia desired, individual tolerance, and physical condition of the patient - Regional anesthesia: epidural, partial to moderate motor blockade, 10 to 20 mL (25 to -50 mg) of a 0.25% solution; moderate to complete motor blockade, 10 to 20 mL (50 to 100 mg) as a 0.5% solution; complete motor blockade, 10 to 20 mL (75 to 150 mg) as a 0.75% solution; repeat once every 3 hours as needed - Regional anesthesia: (obstetrical) hyperbaric spinal (bupivacaine in dextrose formulation only), normal vaginal delivery, 0.8 mL (6 mg) bupivacaine in dextrose as 0.75% solution; cesarean section, 1 to 1.4 mL (7.5 to 10.5 mg) bupivacaine in dextrose as 0.75% solution - Regional anesthesia: hyperbaric spinal (bupivacaine in dextrose formulation only), lower extremity and perineal procedures, 1 mL (7.5 mg) bupivacaine in dextrose as 0.75% solution; lower abdominal procedures, 1.6 mL (12 mg) bupivacaine in dextrose as 0.75% solution; upper abdominal surgery, 2 mL (15 mg) bupivacaine in dextrose, in horizontal position - Regional anesthesia: peripheral nerve block, moderate to complete motor blockade, 5 to 37.5 mL (25 to 175 mg) of 0.5% solution OR 5 to 70 mL (12.5 to 175 mg) of 0.25% solution, repeat every 3 hours if necessary - Regional anesthesia: sympathetic nerve block, 20 to 50 mL (50 to 125 mg) of 0.25% solution, repeat once every 3 hours as needed ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Pain ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Bupivacaine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Administration in children younger than 12 years is not recommended - Bupivacaine spinal with dextrose not recommended in children younger than 18 years - Administration of analgesic, Local: intrapleural, continuous infusion 0.25% bupivacaine with epinephrine at 0.5 mL/kg/hr. - Administration of analgesic, Regional: (body weight 10 kg or less) caudal, single dose 1 to 1.25 mg/kg as a 0.125% or 0.25% solution - Administration of analgesic, Regional: (body weight 10 kg or less) caudal, continuous infusion 0.1 to 0.2 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution; max 0.2 mg/kg/hr - Administration of analgesic, Regional: (body weight 10 kg or less) caudal or epidural, single dose 1 to 1.25 mg/kg as a 0.125% or 0.25% solution - Administration of analgesic, Regional: (body weight 10 kg or less) caudal or epidural, continuous infusion 0.1 to 0.2 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution; max 0.2 mg/kg/hr - Administration of analgesic, Regional: (body weight greater than 10 kg) caudal, single dose 1 to 2.5 mg/kg as a 0.125% or 0.25% solution - Administration of analgesic, Regional: (body weight greater than 10 kg) caudal, continuous infusion 0.2 to 0.4 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution, max 0.4 mg/kg/hr - Anesthesia - Dental procedure: (12 years or older) 1.8 to 3.6 mL of 0.5% solution (9 to 18 mg) with epinephrine; a second dose (9 mg) may be administered; max total dose 90 mg - Anesthesia for procedures on eye: (12 years or older) complete motor blockade, 2 to 4 mL (15 to 30 mg) of 0.75% solution - Local anesthesia: infiltration, 0.5 to 2.5 mg/kg as a 0.25% or 0.5% solution; MAX 1 mL/kg of 0.25% solution, 0.5 mL/kg of 0.5% solution - Local anesthesia: sacral epidural block, (body weight greater than 10 kg) single dose 1 to 2.5 mg/kg as a 0.125% or 0.25% solution - Local anesthesia: sacral epidural block, (body weight greater than 10 kg) continuous infusion 0.2 to 0.4 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution, max 0.4 mg/kg/hr - Regional anesthesia: epidural, (body weight greater than 10 kg) single dose 1 to 2.5 mg/kg as a 0.125% or 0.25% solution - Regional anesthesia: epidural, (body weight greater than 10 kg) continuous infusion 0.2 to 0.4 mg/kg/hr as a 0.1%, 0.125%, or 0.25% solution, MAX 0.4 mg/kg/hr - Regional anesthesia: hyperbaric spinal (bupivacaine in dextrose formulation only), 0.3 to 0.6 mg/kg bupivacaine in dextrose as a 0.75% solution - Regional anesthesia: peripheral nerve block, 0.3 to 2.5 mg/kg as a 0.25% or 0.5% solution; max 1 mL/kg of 0.25% solution, 0.5 mL/kg of 0.5% solution ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Bupivacaine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Bupivacaine in pediatric patients. # Contraindications - Bupivacaine Spinal is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type. - The following conditions preclude the use of spinal anesthesia: - Severe hemorrhage, severe hypotension or shock and arrhythmias, such as complete heart block, which severely restrict cardiac output. - Local infection at the site of proposed lumbar puncture. - Septicemia. # Warnings - Local anesthetics should only be employed by clinicians who are well versed in diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. (see also adverse reactions and precautions.) delay in proper management of dose-related toxicity, underventilation from any cause and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death. - Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. - Spinal anesthetics should not be injected during uterine contractions, because spinal fluid current may carry the drug further cephalad than desired. - A free flow of cerebrospinal fluid during the performance of spinal anesthesia is indicative of entry into the subarachnoid space. However, aspiration should be performed before the anesthetic solution is injected to confirm entry into the subarachnoid space and to avoid intravascular injection. - Bupivacaine solutions containing epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of Bupivacaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. - Until further experience is gained in patients younger than 18 years, administration of Bupivacaine in this age group is not recommended. - Mixing or the prior or intercurrent use of any other local anesthetic with Bupivacaine cannot be recommended because of insufficient data on the clinical use of such mixtures. # Adverse Reactions ## Clinical Trials Experience - Reactions to bupivacaine are characteristic of those associated with other amide-type local anesthetics. - The most commonly encountered acute adverse experiences which demand immediate countermeasures following the administration of spinal anesthesia are hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia. These may lead to cardiac arrest if untreated. In addition, dose-related convulsions and cardiovascular collapse may result from diminished tolerance, rapid absorption from the injection site, or from unintentional intravascular injection of a local anesthetic solution. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. - Respiratory paralysis or underventilation may be noted as a result of upward extension of the level of spinal anesthesia and may lead to secondary hypoxic cardiac arrest if untreated. Preanesthetic medication, intraoperative analgesics and sedatives, as well as surgical manipulation, may contribute to underventilation. This will usually be noted within minutes of the injection of spinal anesthetic solution, but because of differing maximal onset times, differing intercurrent drug usage and differing surgical manipulation, it may occur at any time during surgery or the immediate recovery period. - Hypotension due to loss of sympathetic tone is a commonly encountered extension of the clinical pharmacology of spinal anesthesia. This is more commonly observed in elderly patients, particularly those with hypertension, and patients with shrunken blood volume, shrunken interstitial fluid volume, cephalad spread of the local anesthetic, and/or mechanical obstruction of venous return. Nausea and vomiting are frequently associated with hypotensive episodes following the administration of spinal anesthesia. High doses, or inadvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, bradycardia, heart block, ventricular arrhythmias, and, possibly, cardiac arrest. (See Warnings, Precautions, and Overdosage sections.) - Respiratory paralysis or underventilation secondary to cephalad spread of the level of spinal anesthesia (see Respiratory System) and hypotension for the same reason (see Cardiovascular System) are the two most commonly encountered central nervous system-related adverse observations which demand immediate countermeasures. - High doses or inadvertent intravascular injection may lead to high plasma levels and related central nervous system toxicity characterized by excitement and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. - The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. - Neurologic effects following spinal anesthesia may include loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness and paralysis of the lower extremities, and loss of sphincter control all of which may have slow, incomplete, or no recovery; hypotension, high or total spinal block; urinary retention; headache; backache; septic meningitis, meningismus; arachnoiditis; slowing of labor; increased incidence of forceps delivery; shivering; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid; and fecal and urinary incontinence. - Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and, possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. - Nausea and vomiting may occur during spinal anesthesia. ## Postmarketing Experience There is limited information regarding Bupivacaine Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Bupivacaine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well-controlled studies in pregnant women. Bupivacaine Spinal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of Bupivacaine Spinal at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.) - Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are approximately 30-times the daily maximum recommended human dose (MRHD) of 12 mg/day on a mg dose/m2 body surface area (BSA) basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level being approximately 8-times the MRHD on a BSA basis. - In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg, decreased pup survival was observed at the high dose. The high dose is approximately 30-times the daily MRHD of 12 mg/day on a BSA basis. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bupivacaine in women who are pregnant. ### Labor and Delivery - Spinal anesthesia has a recognized use during labor and delivery. Bupivacaine hydrochloride, when administered properly, via the epidural route in doses 10 to 12 times the amount used in spinal anesthesia has been used for obstetrical analgesia and anesthesia without evidence of adverse effects on the fetus. - Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. - It is extremely important to avoid aortocaval compression by the gravid uterus during administrations of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left. - Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. - The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine. - There have been reports of cardiac arrest during use of Bupivacaine 0.75% solution for epidural anesthesia in obstetrical patients. The package insert for Bupivacaine hydrochloride for epidural, nerve block, etc., has a more complete discussion of preparation for, and management of, this problem. These cases are compatible with systemic toxicity following unintended intravascular injection of the much larger doses recommended for epidural anesthesia and have not occurred within the dose range of bupivacaine hydrochloride 0.75% recommended for spinal anesthesia in obstetrics. The 0.75% concentration of Bupivacaine is therefore not recommended for obstetrical epidural anesthesia. Bupivacaine Spinal (bupivacaine hydrochloride in dextrose injection) is recommended for spinal anesthesia in obstetrics. ### Nursing Mothers - Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue nursing or not administer bupivacaine, taking into account the importance of the drug to the mother. ### Pediatric Use - Until further experience is gained in patients younger than 18 years, administration of Bupivacaine Spinal in this age group is not recommended. ### Geriatic Use - Patients over 65 years, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing spinal anesthesia with Bupivacaine Spinal. (See Precautions, General And Adverse Reactions, Cardiovascular System.) - Elderly patients may require lower doses of Bupivacaine Spinal. (See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION.) - In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. (See Clinical Pharmacology, Pharmacokinetics.) - This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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. (See Clinical Pharmacology, Pharmacokinetics.) ### Gender There is no FDA guidance on the use of Bupivacaine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Bupivacaine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Bupivacaine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Bupivacaine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Bupivacaine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Bupivacaine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Bupivacaine Administration in the drug label. ### Monitoring There is limited information regarding Bupivacaine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Bupivacaine and IV administrations. # Overdosage - Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use or to underventilation (and perhaps apnea) secondary to upward extension of spinal anesthesia. Hypotension is commonly encountered during the conduct of spinal anesthesia due to relaxation of sympathetic tone, and sometimes, contributory mechanical obstruction of venous return. - The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. - The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to a high or total spinal, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred. - If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). - Hypotension due to sympathetic relaxation may be managed by giving intravenous fluids (such as isotonic saline or lactated Ringer’s solution), in an attempt to relieve mechanical obstruction of venous return, or by using vasopressors (such as ephedrine which increases the force of myocardial contractions) and, if indicated, by giving plasma expanders or whole blood. - Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated. - Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. - If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to a high or total spinal may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary. Recovery has been reported after prolonged resuscitative efforts. - The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. - The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg to 8 mg/kg and 38 mg/kg to 54 mg/kg respectively. # Pharmacology ## Mechanism of Action - Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: - Pain, - Temperature, - Touch, - Proprioception, - Skeletal muscle tone. - Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended direct intravascular injection of bupivacaine. Therefore, when epidural anesthesia with bupivacaine is considered, incremental dosing is necessary. - Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage. ## Structure - Bupivacaine hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula: - BupivacaineTM Spinal is available in sterile hyperbaric solution for subarachnoid injection (spinal block). - Bupivacaine hydrochloride is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. - Each mL of Bupivacaine Spinal contains 7.5 mg bupivacaine hydrochloride (anhydrous) and 82.5 mg dextrose (anhydrous). The pH of this solution is adjusted to between 4.0 and 6.5 with sodium hydroxide or hydrochloric acid. - The specific gravity of Bupivacaine Spinal is between 1.030 and 1.035 at 25°C and 1.03 at 37°C. - Bupivacaine Spinal does not contain any preservatives. ## Pharmacodynamics There is limited information regarding Bupivacaine Pharmacodynamics in the drug label. ## Pharmacokinetics - The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma concentration of Bupivacaine, permitting the use of moderately larger total doses and sometimes prolonging the duration of action. - The onset of action with Bupivacaine is rapid and anesthesia is long lasting. The duration of anesthesia is significantly longer with Bupivacaine than with any other commonly used local anesthetic. It has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesics is reduced. - The onset of sensory blockade following spinal block with Bupivacaine Spinal is very rapid (within one minute); maximum motor blockade and maximum dermatome level are achieved within 15 minutes in most cases. Duration of sensory blockade (time to return of complete sensation in the operative site or regression of two dermatomes) following a 12 mg dose averages 2 hours with or without 0.2 mg epinephrine. The time to return of complete motor ability with 12 mg Bupivacaine Spinal averages 3 1/2 hours without the addition of epinephrine and 4 1/2 hours if 0.2 mg epinephrine is added. When compared to equal milligram doses of hyperbaric tetracaine, the duration of sensory blockade was the same but the time to complete motor recovery was significantly longer for tetracaine. Addition of 0.2 mg epinephrine significantly prolongs the motor blockade and time to first postoperative narcotic with Bupivacaine Spinal. - Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by: - The degree of plasma protein binding, - The degree of ionization, and - The degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. - Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. - Pharmacokinetic studies on the plasma profiles of Bupivacaine after direct intravenous injection suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized. - Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of Bupivacaine in adults is 2.7 hours and in neonates 8.1 hours. In clinical studies, elderly patients exhibited a greater spread and higher maximal level of analgesia than younger patients. Elderly patients also reached the maximal level of analgesia more rapidly than younger patients, and exhibited a faster onset of motor blockade. The total plasma clearance was decreased and the terminal half-life was lengthened in these patients. - Amide-type local anesthetics such as Bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecolylxylidine is the major metabolite of Bupivacaine. - The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine. - When administered in recommended doses and concentrations, Bupivacaine does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia. ## Nonclinical Toxicology There is limited information regarding Bupivacaine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Bupivacaine Clinical Studies in the drug label. # How Supplied - Single-dose ampuls of 2 mL (15 mg bupivacaine hydrochloride with 165 mg dextrose), is supplied as follows: ## Storage - Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of spinal anesthesia. Also, when appropriate, the physician should discuss other information including adverse reactions in the Bupivacaine Spinal package insert. # Precautions with Alcohol Alcohol-Bupivacaine 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 Bupivacaine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Bupivacaine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Bupivacaine
a2c48eb332efe909df40c04e3a0f48a598790721	wikidoc	Glossodynia	Glossodynia # Overview Glossodynia or burning mouth syndrome (BMS) is a condition characterized by a burning or tingling sensation on the lips, tongue, or entire mouth. Typically, there are no visual signs like discoloration that help the diagnosis. Possible causes include nutritional deficiencies, chronic anxiety or depression, type 2 diabetes, menopause, oral disorders such as thrush or dry mouth, or damaged nerves (specifically, cranial nerves associated with taste). This conditions appears more often in women, specifically women after menopause, than men. Pain typically is low or nonexistent in the morning and builds up over the course of the day. Low dosages of benzodiazepines, tricyclic antidepressants or anticonvulsants may prove to be an effective treatment. ## Life Threatening Causes ## Common Causes ## Causes by Organ System ## Causes in Alphabetical Order - ↑ Ann M. Gillenwater, Nadarajah Vigneswaran, Hanadi Fatani, Pierre Saintigny & Adel K. El-Naggar (2013). "Proliferative verrucous leukoplakia (PVL): a review of an elusive pathologic entity!". Advances in anatomic pathology. 20 (6): 416–423. doi:10.1097/PAP.0b013e3182a92df1. PMID 24113312. Unknown parameter \|month= ignored (help)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} - ↑ Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. (2006). "Idiosyncratic drug-induced agranulocytosis: Update of an old disorder". Eur J Intern Med. 17 (8): 529–35. Text "pmid 17142169" ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ title="By Internet Archive Book Images , via Wikimedia Commons" href=":A_manual_of_syphilis_and_the_venereal_diseases%2C_(1900)_(14595882378).jpg" - ↑ Feikin DR, Lezotte DC, Hamman RF, Salmon DA, Chen RT, Hoffman RE (2000). "Individual and community risks of measles and pertussis associated with personal exemptions to immunization". JAMA. 284 (24): 3145–50. PMID 11135778.CS1 maint: Multiple names: authors list (link) - ↑ Ratnam S, West R, Gadag V, Williams B, Oates E (1996). "Immunity against measles in school-aged children: implications for measles revaccination strategies". Can J Public Health. 87 (6): 407–10. PMID 9009400.CS1 maint: Multiple names: authors list (link)	Glossodynia Template:DiseaseDisorder infobox Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Glossodynia or burning mouth syndrome (BMS) is a condition characterized by a burning or tingling sensation on the lips, tongue, or entire mouth. Typically, there are no visual signs like discoloration that help the diagnosis. Possible causes include nutritional deficiencies, chronic anxiety or depression, type 2 diabetes, menopause, oral disorders such as thrush or dry mouth, or damaged nerves (specifically, cranial nerves associated with taste). This conditions appears more often in women, specifically women after menopause, than men. Pain typically is low or nonexistent in the morning and builds up over the course of the day. Low dosages of benzodiazepines, tricyclic antidepressants or anticonvulsants may prove to be an effective treatment. ## Life Threatening Causes ## Common Causes ## Causes by Organ System ## Causes in Alphabetical Order - ↑ Ann M. Gillenwater, Nadarajah Vigneswaran, Hanadi Fatani, Pierre Saintigny & Adel K. El-Naggar (2013). "Proliferative verrucous leukoplakia (PVL): a review of an elusive pathologic entity!". Advances in anatomic pathology. 20 (6): 416–423. doi:10.1097/PAP.0b013e3182a92df1. PMID 24113312. Unknown parameter \|month= ignored (help)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} - ↑ Andrès E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. (2006). "Idiosyncratic drug-induced agranulocytosis: Update of an old disorder". Eur J Intern Med. 17 (8): 529–35. Text "pmid 17142169" ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ title="By Internet Archive Book Images [No restrictions], via Wikimedia Commons" href="https://commons.wikimedia.org/wiki/File:A_manual_of_syphilis_and_the_venereal_diseases%2C_(1900)_(14595882378).jpg" - ↑ Feikin DR, Lezotte DC, Hamman RF, Salmon DA, Chen RT, Hoffman RE (2000). "Individual and community risks of measles and pertussis associated with personal exemptions to immunization". JAMA. 284 (24): 3145–50. PMID 11135778.CS1 maint: Multiple names: authors list (link) - ↑ Ratnam S, West R, Gadag V, Williams B, Oates E (1996). "Immunity against measles in school-aged children: implications for measles revaccination strategies". Can J Public Health. 87 (6): 407–10. PMID 9009400.CS1 maint: Multiple names: authors list (link)	https://www.wikidoc.org/index.php/Burning_mouth_syndrome
f8ceb8d92306e0eeecccdc7d9fbb8930dcc4079a	wikidoc	Trepanation	Trepanation Trepanation (also known as trepanning, trephination, trephining or burr hole) is surgery in which a hole is drilled or scraped into the skull, thus exposing the dura mater in order to treat health problems related to intracranial diseases, though in the modern era it is used only to treat epidural and subdural hematomas, as an extreme body modification, and for surgical access for certain other neurosurgical procedures, such as intracranial pressure monitoring. Trepanation was carried out for both medical reasons and mystical practices for a long time: evidence of trepanation has been found in prehistoric human remains from Neolithic times onwards, per cave paintings indicating that people believed the practice would cure epileptic seizures, migraines, and mental disorders. Furthermore, Hippocrates gave specific directions on the procedure from its evolution through the Greek age. The modern medical procedure of corneal transplant surgery uses a technique known as trepanning or trephining, however the operation is conducted on the eye (not the skull), with an instrument called a trephine. # History of trepanation ## Trepanation in the Old World See also Prehistoric Medicine Trepanation is perhaps the oldest surgical procedure for which there is evidence, and in some areas may have been quite widespread. Out of 120 prehistoric skulls found at one burial site in France dated to 6500 BC, 40 had trepanation holes. Surprisingly, many prehistoric and premodern patients had signs of their skull structure healing; suggesting that many of those that proceeded with the surgery survived their operation. Trepanation was also practiced in the classical and Renaissance periods. Hippocrates gave specific directions on the procedure from its evolution through the Greek age, and Galen elaborates on the procedure, too. Doctors in ancient Egypt used the scrapings of the skull to create love potions and other concoctions. During the Middle Ages and the Renaissance, trepanation was practiced as a cure for various ailments, including seizures and skull fractures. The surgeons who performed these trepanations were probably highly skilled because the survival rate of the operations was high and the infection rate was low. ## Trepanation in pre-Columbian Mesoamerica In pre-Columbian Mesoamerica, evidence for the practice of trepanation and an assortment of other cranial deformation techniques comes from a variety of sources, including physical cranial remains of pre-Columbian burials, allusions in iconographic artworks and reports from the post-colonial period. Among New World societies, trephinning is most commonly found in the Andean civilizations such as the Inca. Its prevalence among Mesoamerican civilizations is much lower, at least judging from the comparatively few trepanated crania which have been uncovered. The archaeological record in Mesoamerica is further complicated by the practice of skull mutilation and modification which was carried out after the death of the subject, in order to fashion "trophy skulls" and the like of captives and enemies. This was a reasonably widespread tradition, illustrated in pre-Columbian art which on occasion depicts rulers adorned with or carrying the modified skulls of their defeated enemies, or of the ritualistic display of sacrificial victims. Several Mesoamerican cultures used a skull-rack (known by its Nahuatl term, tzompantli ) on which skulls were impaled in rows or columns of wooden stakes. Even so, some evidence of genuine trepanation in Mesoamerica (i.e., where the subject was living) has been recovered. The earliest archaeological survey published of trepanated crania was a late 19th-century study of several specimens recovered from the Tarahumara mountains by the Norwegian ethnographer Carl Lumholtz. Later studies documented cases identified from a range of sites in Oaxaca and central Mexico, such as Tilantongo, Oaxaca and the major Zapotec site of Monte Albán. Two specimens from the Tlatilco civilization's homelands (which flourished around 1400 BCE) indicate the practice has a lengthy tradition. A study of ten low-status burials from the Late Classic period at Monte Albán concluded that the trepanation had been applied non-therapeutically, and, since multiple techniques had been used and since some people had received more than one trepanation, concluded it had been done experimentally. Inferring the events to represent experiments on people until they died, the study interpreted that use of trepanation as an indicator of the stressful sociopolitical climate that not long thereafter resulted in the abandonment of Monte Alban as the primary regional administrative center in the Oaxacan highlands. Specimens identified from the Maya civilization region of southern Mexico, Guatemala and the Yucatán Peninsula show no evidence of the drilling or cutting techniques found in central and highland Mexico. Instead, the pre-Columbian Maya seemed to have utilised an abrasive technique which ground away at the back of the skull, thinning the bone and sometimes perforating it, similar to the examples from Cholula. Many of the skulls from the Maya region date from the Postclassic period (ca. 950–1400), and include specimens found at Palenque in Chiapas, and recovered from the Sacred Cenote at the prominent Postclassic site of Chichen Itza in northern Yucatán. # Trepanation in modern medicine Trepanation is a widely accepted treatment for epidural and subdural hematomas, and for surgical access for certain other neurosurgical procedures, such as intracranial pressure monitoring. Modern surgeons generally use the term craniotomy for this procedure. In almost all cases, the removed piece of skull is replaced as soon as possible. If the bone is not replaced, then the procedure is considered a craniectomy. # Voluntary trepanation Although considered today to be pseudoscience, the practice of trepanation for other purported medical benefits continues. The most prominent explanation for these benefits is offered by Bart Huges (also known as Hughes), sometimes referred to as "Dr. Bart Hughes" even though he did not complete his medical degree. Hughes claims that trepanation increases "brain blood volume" and thereby enhances cerebral metabolism in a manner similar to cerebral vasodilators such as gingko biloba. No published results of clinical trials of trepanation have supported these claims. There is an ongoing study involving pre and post operative MRI in a Mexican cosmetic surgery clinic. Publication of this study is uncertain. Other modern practitioners of trepanation claim that it holds other medical benefits, such as a treatment for depression or other psychological ailments. In 2000 two men from Cedar City, Utah were prosecuted for practicing medicine without a license after they performed a trepanation on an English woman to treat her chronic fatigue syndrome and depression. However, most individuals who practice non-emergency trepanation today do so for psychic purposes. A prominent proponent of the modern view is Peter Halvorson, who drilled a hole in the front of his own skull to increase "brain blood volume". Amanda Feilding performed a self-trepanation with a drill, while her partner Joey Mellen filmed the operation, in the film titled Heartbeat in the Brain. The film has since been lost. In a chapter of his book, Eccentric Lives & Peculiar Notions, John Michell describes a British group that advocates self-trepanation, that is, the drilling of a hole in the skull to allow the brain access to more space and oxygen. The chapter is called "The People With Holes in their Heads". According to Michell, the Dutchman Bart Huges (sometimes written as "Bart Hughes") pioneered the idea of trepanation. Huges' 1962 monograph, Homo Sapiens Correctus, is cited by most advocates of self-trepanation. Among other arguments, he contends that since children have a higher state of consciousness, and children's skulls are not fully closed, that one can return to an earlier, childlike state of consciousness by self-trepanation. Further, by allowing the brain to freely pulsate, Huges argues that a number of benefits will accrue. Michell quotes a book called Bore Hole written by Joseph (Joey) Mellen. At the time the passage below was written, Joey and his partner, Amanda Feilding, had made two previous attempts at trepanning Joey. The second attempt ended up placing Joey in the hospital, where he was scolded severely and sent for psychiatric evaluation. After he returned home, Joey decided to try again. Joey describes his third attempt at self-trepanation: There is an active advocacy group for the self-trepanation procedure, the International Trepanation Advocacy Group. Their webpage includes MRI images of trepanned brains. # Miscellaneous references - A Hole in the Head is the 1998 documentary made about trepanation. - In David Cronenberg's 1981 psychological thriller film Scanners, the leader of the rogue 'Scanner' organisation, Darryl Revok, practiced self trepanation to relieve the pressure of the telepathic voices in his head. - In Philip Pullman's fantasy series His Dark Materials, trepanning is used by the Tartars to increase consciousness by attracting the mysterious substance called Dust. - The movie π directed by Darren Aronofsky contains a somewhat graphic self-trepanation scene performed with an electric drill. - The movie Saw III also contains a graphic trepanation scene. - In the 2003 film Master and Commander: The Far Side of the World ship surgeon Stephen Maturin performs a trepanation on Joe Plaice whose skull was fractured by a falling piece of the yard arms. - In the manga and anime One Piece trepanation is mentioned by the doctor Tony Tony Chopper as a method for treating tumours used in ancient times when analysing a skull they found in the wrecks of a pirate ship which fell from the sky. - "Trephination" is a song by the trash metal band Machine Head. - "Trepanning" is a song by the rock band Cave In. - "Trepanation" is also the term used to refer to the process by which the steel in turbine rotors is tested for quality after forging. - The band Ned's Atomic Dustbin named their 1995 album Brainbloodvolume. The album included a song named "Borehole". - In the novel Dracula, Abraham Van Helsing uses trepanation to treat the haemorrhage Renfield received when Count Dracula flung him to the ground, in order to bring him back to consciousness. - In the movie Frankenhooker, Jeffrey Franken (played by James Lorinz) trepans himself with a power drill to calm himself. - In the movie Ghostbusters, Peter Venkman refers to a past incident when Egon attempted to drill a hole in his own head. Egon replies 'It would have worked if you hadn't stopped me.' - In the movie X2: X-Men United, it is mentioned that the mother of Ronelio Ramil has drilled a hole in her head to drill out the visions that her son continuously projects into her mind. She did not survive the procedure. - On the show Dead Like Me, Mason dies and becomes a grim reaper after attempting trepanation on himself while "chasing the ultimate high." - On the fourth season House episode "Frozen", Dr. Cate Milton (Mira Sorvino) undergoes a trepanning operation (with a drill press) at the South Pole conducted via webcam. - On the third season of Grey's Anatomy, Izzie drills burr holes into a patient's head at a ferry boat crash scene. - On the HBO/BBC series "Rome" season 1, episode 2 the character Titus Pullo undegoes the procedure to relieve him of swelling and to remove a jar fragment from his skull. WARNING: This is an extremely graphic showing of the procedure.	Trepanation Trepanation (also known as trepanning, trephination, trephining or burr hole) is surgery in which a hole is drilled or scraped into the skull, thus exposing the dura mater in order to treat health problems related to intracranial diseases, though in the modern era it is used only to treat epidural and subdural hematomas, as an extreme body modification, and for surgical access for certain other neurosurgical procedures, such as intracranial pressure monitoring. Trepanation was carried out for both medical reasons and mystical practices for a long time: evidence of trepanation has been found in prehistoric human remains from Neolithic times onwards, per cave paintings indicating that people believed the practice would cure epileptic seizures, migraines, and mental disorders.[1] Furthermore, Hippocrates gave specific directions on the procedure from its evolution through the Greek age. The modern medical procedure of corneal transplant surgery uses a technique known as trepanning or trephining, however the operation is conducted on the eye (not the skull), with an instrument called a trephine. # History of trepanation ## Trepanation in the Old World See also Prehistoric Medicine Trepanation is perhaps the oldest surgical procedure for which there is evidence,[2] and in some areas may have been quite widespread. Out of 120 prehistoric skulls found at one burial site in France dated to 6500 BC, 40 had trepanation holes.[3] Surprisingly, many prehistoric and premodern patients had signs of their skull structure healing; suggesting that many of those that proceeded with the surgery survived their operation. Trepanation was also practiced in the classical and Renaissance periods. Hippocrates gave specific directions on the procedure from its evolution through the Greek age, and Galen elaborates on the procedure, too. Doctors in ancient Egypt used the scrapings of the skull to create love potions and other concoctions. During the Middle Ages and the Renaissance, trepanation was practiced as a cure for various ailments, including seizures and skull fractures. The surgeons who performed these trepanations were probably highly skilled because the survival rate of the operations was high and the infection rate was low.[4] ## Trepanation in pre-Columbian Mesoamerica In pre-Columbian Mesoamerica, evidence for the practice of trepanation and an assortment of other cranial deformation techniques comes from a variety of sources, including physical cranial remains of pre-Columbian burials, allusions in iconographic artworks and reports from the post-colonial period. Among New World societies, trephinning is most commonly found in the Andean civilizations such as the Inca.[5] Its prevalence among Mesoamerican civilizations is much lower, at least judging from the comparatively few trepanated crania which have been uncovered.[6] The archaeological record in Mesoamerica is further complicated by the practice of skull mutilation and modification which was carried out after the death of the subject, in order to fashion "trophy skulls" and the like of captives and enemies. This was a reasonably widespread tradition, illustrated in pre-Columbian art which on occasion depicts rulers adorned with or carrying the modified skulls of their defeated enemies, or of the ritualistic display of sacrificial victims. Several Mesoamerican cultures used a skull-rack (known by its Nahuatl term, tzompantli ) on which skulls were impaled in rows or columns of wooden stakes. Even so, some evidence of genuine trepanation in Mesoamerica (i.e., where the subject was living) has been recovered. The earliest archaeological survey[7] published of trepanated crania was a late 19th-century study of several specimens recovered from the Tarahumara mountains by the Norwegian ethnographer Carl Lumholtz.[8] Later studies documented cases identified from a range of sites in Oaxaca and central Mexico, such as Tilantongo, Oaxaca and the major Zapotec site of Monte Albán. Two specimens from the Tlatilco civilization's homelands (which flourished around 1400 BCE) indicate the practice has a lengthy tradition.[9] A study of ten low-status burials from the Late Classic period at Monte Albán concluded that the trepanation had been applied non-therapeutically, and, since multiple techniques had been used and since some people had received more than one trepanation, concluded it had been done experimentally. Inferring the events to represent experiments on people until they died, the study interpreted that use of trepanation as an indicator of the stressful sociopolitical climate that not long thereafter resulted in the abandonment of Monte Alban as the primary regional administrative center in the Oaxacan highlands. Specimens identified from the Maya civilization region of southern Mexico, Guatemala and the Yucatán Peninsula show no evidence of the drilling or cutting techniques found in central and highland Mexico. Instead, the pre-Columbian Maya seemed to have utilised an abrasive technique which ground away at the back of the skull, thinning the bone and sometimes perforating it, similar to the examples from Cholula. Many of the skulls from the Maya region date from the Postclassic period (ca. 950–1400), and include specimens found at Palenque in Chiapas, and recovered from the Sacred Cenote at the prominent Postclassic site of Chichen Itza in northern Yucatán.[10] # Trepanation in modern medicine Trepanation is a widely accepted treatment for epidural and subdural hematomas, and for surgical access for certain other neurosurgical procedures, such as intracranial pressure monitoring. Modern surgeons generally use the term craniotomy for this procedure. In almost all cases, the removed piece of skull is replaced as soon as possible. If the bone is not replaced, then the procedure is considered a craniectomy. # Voluntary trepanation Although considered today to be pseudoscience, the practice of trepanation for other purported medical benefits continues. The most prominent explanation for these benefits is offered by Bart Huges (also known as Hughes), sometimes referred to as "Dr. Bart Hughes" even though he did not complete his medical degree. Hughes claims that trepanation increases "brain blood volume" and thereby enhances cerebral metabolism in a manner similar to cerebral vasodilators such as gingko biloba. No published results of clinical trials of trepanation have supported these claims. There is an ongoing study involving pre and post operative MRI in a Mexican cosmetic surgery clinic.[1] Publication of this study is uncertain. Other modern practitioners of trepanation claim that it holds other medical benefits, such as a treatment for depression or other psychological ailments. In 2000 two men from Cedar City, Utah were prosecuted for practicing medicine without a license after they performed a trepanation on an English woman to treat her chronic fatigue syndrome and depression.[2] However, most individuals who practice non-emergency trepanation today do so for psychic purposes. A prominent proponent of the modern view is Peter Halvorson, who drilled a hole in the front of his own skull to increase "brain blood volume".[11] Amanda Feilding performed a self-trepanation with a drill, while her partner Joey Mellen filmed the operation, in the film titled Heartbeat in the Brain. The film has since been lost. In a chapter of his book, Eccentric Lives & Peculiar Notions, John Michell describes a British group that advocates self-trepanation, that is, the drilling of a hole in the skull to allow the brain access to more space and oxygen. The chapter is called "The People With Holes in their Heads". According to Michell, the Dutchman Bart Huges (sometimes written as "Bart Hughes") pioneered the idea of trepanation. Huges' 1962 monograph, Homo Sapiens Correctus, is cited by most advocates of self-trepanation. Among other arguments, he contends that since children have a higher state of consciousness, and children's skulls are not fully closed, that one can return to an earlier, childlike state of consciousness by self-trepanation. Further, by allowing the brain to freely pulsate, Huges argues that a number of benefits will accrue. Michell quotes a book called Bore Hole written by Joseph (Joey) Mellen. At the time the passage below was written, Joey and his partner, Amanda Feilding, had made two previous attempts at trepanning Joey. The second attempt ended up placing Joey in the hospital, where he was scolded severely and sent for psychiatric evaluation. After he returned home, Joey decided to try again. Joey describes his third attempt at self-trepanation: There is an active advocacy group for the self-trepanation procedure, the International Trepanation Advocacy Group. Their webpage [3] includes MRI images of trepanned brains. # Miscellaneous references - A Hole in the Head is the 1998 documentary made about trepanation. - In David Cronenberg's 1981 psychological thriller film Scanners, the leader of the rogue 'Scanner' organisation, Darryl Revok, practiced self trepanation to relieve the pressure of the telepathic voices in his head. - In Philip Pullman's fantasy series His Dark Materials, trepanning is used by the Tartars to increase consciousness by attracting the mysterious substance called Dust. - The movie π directed by Darren Aronofsky contains a somewhat graphic self-trepanation scene performed with an electric drill. - The movie Saw III also contains a graphic trepanation scene. - In the 2003 film Master and Commander: The Far Side of the World ship surgeon Stephen Maturin performs a trepanation on Joe Plaice whose skull was fractured by a falling piece of the yard arms. - In the manga and anime One Piece trepanation is mentioned by the doctor Tony Tony Chopper as a method for treating tumours used in ancient times when analysing a skull they found in the wrecks of a pirate ship which fell from the sky. - "Trephination" is a song by the trash metal band Machine Head. - "Trepanning" is a song by the rock band Cave In. - "Trepanation" is also the term used to refer to the process by which the steel in turbine rotors is tested for quality after forging.[citation needed] - The band Ned's Atomic Dustbin named their 1995 album Brainbloodvolume. The album included a song named "Borehole". - In the novel Dracula, Abraham Van Helsing uses trepanation to treat the haemorrhage Renfield received when Count Dracula flung him to the ground, in order to bring him back to consciousness. - In the movie Frankenhooker, Jeffrey Franken (played by James Lorinz) trepans himself with a power drill to calm himself. - In the movie Ghostbusters, Peter Venkman refers to a past incident when Egon attempted to drill a hole in his own head. Egon replies 'It would have worked if you hadn't stopped me.' - In the movie X2: X-Men United, it is mentioned that the mother of Ronelio Ramil has drilled a hole in her head to drill out the visions that her son continuously projects into her mind. She did not survive the procedure. - On the show Dead Like Me, Mason dies and becomes a grim reaper after attempting trepanation on himself while "chasing the ultimate high." [4] - On the fourth season House episode "Frozen", Dr. Cate Milton (Mira Sorvino) undergoes a trepanning operation (with a drill press) at the South Pole conducted via webcam. - On the third season of Grey's Anatomy, Izzie drills burr holes into a patient's head at a ferry boat crash scene. - On the HBO/BBC series "Rome" season 1, episode 2 the character Titus Pullo undegoes the procedure to relieve him of swelling and to remove a jar fragment from his skull. WARNING: This is an extremely graphic showing of the procedure.	https://www.wikidoc.org/index.php/Burr_hole
7716a635f07d00f0e6370c7741fd33dffe9fff9c	wikidoc	Burt's Bees	Burt's Bees Burt's Bees is an "Earth friendly, Natural Personal Care Company." making products for personal care, health, beauty, and personal hygiene. As of 2007, they manufacture over 150 products for facial and body skin care, lip care, hair care, baby care, men's grooming, and outdoor remedies distributed in nearly 30,000 retail outlets including grocery stores and drug store chains across the US, UK, Ireland, Canada, Hong Kong, and Taiwan from their headquarters in Durham, NC. Burt's Bees manufactures their products with natural ingredients using minimal processing such as distillation/condensation, extraction/steamed distillation/pressure cooking and hydrolysis to maintain the purity of those ingredients. In addition, every product has a "natural bar" which gives a percentage of natural ingredients in that product, often with detailed ingredient descriptions. Burt's Bees operates under a business model referred to as "The Greater Good," which outlines that all company practices must be socially responsible. To reflect this philosophy, Burt's Bees uses all natural ingredients, engages in environmentally friendly business practices, and extends its humanitarian efforts to the community at large. Originating in Maine in the 1980s, the business began by bottling and selling honey, a practice that slowly diminished as the company evolved as a corporation. Eventually, other products using honey and beeswax, including edible spreads and furniture polish, were sold, before moving into the personal care line. # Products All products listed below were from the Burt's Bees product page. - face care (cleansers, exfoliants, toners, moisturizers, skin treatments, eye creams) - lip care (lip balms, lip glosses, lip shimmers) - body care (body washes, soaps, moisturizers, bath oils) - hand care (hand soaps, hand moisturizers) - foot care (foot creams, lotions, pumice stones) - hair care (shampoos, conditioners, hair treatments) - baby care (baby washes and soaps, diaper care, moisturizers) - pregnant mother care (belly moisturizer, leg and foot cream, baby oil) - mens' grooming (body washes, soaps, shaving materials, moisturizers, cologne) - sun and outdoors care (sunscreens, lip balms, body washes, soaps, moisturizers, skin protection, skin irritation products) # Distribution Burt's Bees products come in regular and sample sizes which are available in natural and specialty food markets (e.g. Trader Joe's & Whole Foods Market). In 2005, the traditional pharmacy chains, CVS and Walgreens, began selling the products. They are also sold at Target and Borders Books outlets. # Timeline Burt's Bees originated in Maine as a candle making partnership between Roxanne Quimby and Burt Shavitz in 1984. Shavitz had a honey business which provided the excess beeswax needed for the candles and Quimby's focus on maintaining high quality helped to grow their business from an initial $200 at the Dover-Foxcroft Junior High School craft fair to $20,000 by the end of their first year. Their first headquarters was an abandoned one-room schoolhouse rented out from a friend for $150 a year. Burt's Bees increased production after a New York boutique, Zona, ordered hundreds of their beeswax candles. Forty additional employees were hired and an abandoned bowling alley became their new manufacturing location. During this time, Quimby found a 19th century book of home-made personal care recipes and Burt's Bees entered into the personal care products industry. Burt's Bees became incorporated and had a product offering including candles, natural soaps, perfumes, and eventually lip balm, which became their best-selling product. Quimby bought out Shavitz's shares in the company. Increasing demand and product offerings necessitated a move from Maine headquarters to North Carolina where other personal care product manufacturers were also situated. Burt's Bees changed its focus to exclusively personal care products. The new manufacturing location was in an 18,000 square foot former garment factory in Creedmoor, North Carolina. Automated machines, such as a former cafeteria mixer from Duke University, were introduced to increase production, although Burt's Bees continued to focus on the "home-made" product theme. Chapel Hill was the site of the first Burt's Bees retail store which offered 50 natural personal care products. Distribution and demand of products had also reached the Japanese market. Burt's Bees was offering over 100 natural personal care products in 4,000 locations with sales in excess of $8 million dollars. Distribution had reached higher-end national retailers such as Whole Foods Market and Cracker Barrel. New product offerings branched into travel-sized skin care and hair care products. Again, with increasing demand and an increase product offering including sugar and milk-based body lotions and bath products, Burt's Bees relocated to Durham amongst many other high-tech companies and enterprises in the Research Triangle area of North Carolina. An eCommerce website was launching allowing distribution in a much larger, nationwide scale. Burt's Bees launched its first toothpaste, first shampoo, and successful Baby Bee product line of infant personal care products. Founder, Roxanne Quimby, also used company-earned profits to preserve 185,000 acres of forest land in Maine, marking the beginning of a relationship with The Nature Conservancy, an international organization engaged in environmental protection and conservation. Private equity firm, AEA Investors, purchased 80% of Burt's Bees with co-founder, Roxanne Quimby, retaining a 20% share and a seat on the board. Michael Indursky, a former Garnier and Unilever executive joins Burt's Bees in July to head Burt's Bees marketing and public relations group. John Replogle, a former general manager of Unilever's skin care division, became the Chief Executive Officer and President, effective from January 19, 2006. Prior to joining Unilever, Replogle served as President of Guinness Bass Import Company, Managing Director of Guinness Great Britain and had several roles in Marketing, Sales and Strategy with Diageo. Burt's Bees currently offers over 150 natural personal care products in 30,000 retail locations and sales in excess of $250 million (2006) with satellite offices across the United States, UK, Ireland, Canada, Hong Kong, and Taiwan.	Burt's Bees Template:Cleanup Template:Infobox Company Burt's Bees is an "Earth friendly, Natural Personal Care Company."[1] making products for personal care, health, beauty, and personal hygiene. As of 2007, they manufacture over 150 products for facial and body skin care, lip care, hair care, baby care, men's grooming, and outdoor remedies[2] distributed in nearly 30,000 retail outlets including grocery stores and drug store chains across the US, UK, Ireland, Canada, Hong Kong, and Taiwan from their headquarters in Durham, NC.[3][2] Burt's Bees manufactures their products with natural ingredients[4] using minimal processing such as distillation/condensation, extraction/steamed distillation/pressure cooking and hydrolysis to maintain the purity of those ingredients.[5] In addition, every product has a "natural bar" which gives a percentage of natural ingredients in that product, often with detailed ingredient descriptions.[6] Burt's Bees operates under a business model referred to as "The Greater Good," which outlines that all company practices must be socially responsible. To reflect this philosophy, Burt's Bees uses all natural ingredients,[7] engages in environmentally friendly business practices,[8] and extends its humanitarian efforts to the community at large.[9] Originating in Maine in the 1980s, the business began by bottling and selling honey, a practice that slowly diminished as the company evolved as a corporation.[citation needed] Eventually, other products using honey and beeswax, including edible spreads and furniture polish, were sold, before moving into the personal care line.[citation needed] # Products All products listed below were from the Burt's Bees product page.[3] - face care (cleansers, exfoliants, toners, moisturizers, skin treatments, eye creams) - lip care (lip balms, lip glosses, lip shimmers) - body care (body washes, soaps, moisturizers, bath oils) - hand care (hand soaps, hand moisturizers) - foot care (foot creams, lotions, pumice stones) - hair care (shampoos, conditioners, hair treatments) - baby care (baby washes and soaps, diaper care, moisturizers) - pregnant mother care (belly moisturizer, leg and foot cream, baby oil) - mens' grooming (body washes, soaps, shaving materials, moisturizers, cologne) - sun and outdoors care (sunscreens, lip balms, body washes, soaps, moisturizers, skin protection, skin irritation products) # Distribution Burt's Bees products come in regular and sample sizes which are available in natural and specialty food markets (e.g. Trader Joe's & Whole Foods Market). In 2005, the traditional pharmacy chains, CVS and Walgreens, began selling the products. They are also sold at Target and Borders Books outlets. # Timeline ## 1984 Burt's Bees originated in Maine as a candle making partnership between Roxanne Quimby and Burt Shavitz in 1984. Shavitz had a honey business which provided the excess beeswax needed for the candles and Quimby's focus on maintaining high quality helped to grow their business from an initial $200 at the Dover-Foxcroft Junior High School craft fair to $20,000 by the end of their first year. Their first headquarters was an abandoned one-room schoolhouse rented out from a friend for $150 a year.[10] ## 1989 Burt's Bees increased production after a New York boutique, Zona, ordered hundreds of their beeswax candles. Forty additional employees were hired and an abandoned bowling alley became their new manufacturing location. During this time, Quimby found a 19th century book of home-made personal care recipes and Burt's Bees entered into the personal care products industry.[10] ## 1991 Burt's Bees became incorporated and had a product offering including candles, natural soaps, perfumes, and eventually lip balm, which became their best-selling product.[2] ## 1993 Quimby bought out Shavitz's shares in the company. Increasing demand and product offerings necessitated a move from Maine headquarters to North Carolina where other personal care product manufacturers were also situated. Burt's Bees changed its focus to exclusively personal care products.[2] ## 1994 The new manufacturing location was in an 18,000 square foot former garment factory in Creedmoor, North Carolina. Automated machines, such as a former cafeteria mixer from Duke University, were introduced to increase production, although Burt's Bees continued to focus on the "home-made" product theme. Chapel Hill was the site of the first Burt's Bees retail store which offered 50 natural personal care products. Distribution and demand of products had also reached the Japanese market.[2] ## 1998 Burt's Bees was offering over 100 natural personal care products in 4,000 locations with sales in excess of $8 million dollars. Distribution had reached higher-end national retailers such as Whole Foods Market and Cracker Barrel. New product offerings branched into travel-sized skin care and hair care products.[2] ## 1999 Again, with increasing demand and an increase product offering including sugar and milk-based body lotions and bath products, Burt's Bees relocated to Durham amongst many other high-tech companies and enterprises in the Research Triangle area of North Carolina. An eCommerce website was launching allowing distribution in a much larger, nationwide scale.[2] ## 2002-2003 Burt's Bees launched its first toothpaste, first shampoo, and successful Baby Bee product line of infant personal care products. Founder, Roxanne Quimby, also used company-earned profits to preserve 185,000 acres of forest land in Maine, marking the beginning of a relationship with The Nature Conservancy, an international organization engaged in environmental protection and conservation.[2] ## 2004 Private equity firm, AEA Investors, purchased 80% of Burt's Bees with co-founder, Roxanne Quimby, retaining a 20% share and a seat on the board. [11] ## 2005 Michael Indursky, a former Garnier and Unilever executive joins Burt's Bees in July to head Burt's Bees marketing and public relations group.[12] ## 2006 John Replogle, a former general manager of Unilever's skin care division, became the Chief Executive Officer and President, effective from January 19, 2006. Prior to joining Unilever, Replogle served as President of Guinness Bass Import Company, Managing Director of Guinness Great Britain and had several roles in Marketing, Sales and Strategy with Diageo.[13] ## 2007 Burt's Bees currently offers over 150 natural personal care products in 30,000 retail locations and sales in excess of $250 million (2006)[2] with satellite offices across the United States, UK, Ireland, Canada, Hong Kong, and Taiwan.[2]	https://www.wikidoc.org/index.php/Burt%27s_Bees
32a93e84823a163a82647424b4fb4487c3fe5627	wikidoc	Nicardipine	Nicardipine # 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 Nicardipine is a Calcium Channel Blocker that is FDA approved for the treatment of short-term treatment of hypertension when oral therapy is not feasible or not desirable. Common adverse reactions include Hypotension, Peripheral edema, Tachyarrhythmia, Nausea, Vomiting, Headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information (capsule) - The dose of nicardipine hydrochloride should be individually adjusted according to the blood pressure response. - Initial dosage: 20 mg PO tid. - Dosage range: 20 mg - 40 mg PO tid. The maximum blood pressure lowering effect occurs approximately 1 to 2 hours after dosing. To assess the adequacy of blood pressure response, the blood pressure should be measured at trough (8 hours after dosing). Because of the prominent peak effects of nicardipine, blood pressure should be measured 1 to 2 hours after dosing, particularly during initiation of therapy. - At least 3 days should be allowed before increasing the nicardipine dose to ensure achievement of steady-state plasma drug concentrations. - Dosing information (Injection) - Dosage as a Substitute for Oral Nicardipine Therapy - The intravenous infusion rate required to produce an average plasma concentration equivalent to a given oral dose at steady state is shown in the following table: - Dosage for Initiation of Therapy in a Patient Not Receiving Oral Nicardipine - Initiate dosage: 25 mL/hr (5.0 mg/hr). - If desired blood pressure reduction is not achieved at this dose, the infusion rate may be increased by 12.5 mL/hr (2.5 mg/hr) every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 75 mL/hr (15.0 mg/hr), until desired blood pressure reduction is achieved. - Following achievement of the blood pressure goal utilizing rapid titration, decrease the infusion rate to 15 mL/hr (3 mg/hr). - Drug Discontinuation and Transition to an Oral Antihypertensive Agent - Discontinuation of infusion is followed by a 50% offset of action in about 30 minutes. - If treatment includes transfer to an oral antihypertensive agent other than oral nicardipine, initiate therapy upon discontinuation of Nicardipine I.V.Injection. - If oral nicardipine is to be used, administer the first dose 1 hour prior to discontinuation of the infusion. - Special Populations - Titrate Nicardipine I.V. Injection slowly in patients with heart failure or impaired hepatic or renal function. ### Angina - Dosing information (Capsule only) - Initial dosage: 20 mg PO tid. - Dosage range: 20 mg to 40 mg PO tid. At least 3 days should be allowed before increasing the nicardipine hydrochloride dose to ensure achievement of steady-state plasma drug concentrations. - Concomitant Use With Other Antianginal Agents ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nicardipine in adult patients. ### Non–Guideline-Supported Use ### Electroconvulsive therapy - Dosing information - Not applicable ### Migraine - Dosing information - 20 mg PO tid. - 20 mg PO bid. ### Subarachnoid hemorrhage - Vasospasm - Dosing information - 0.15 mg/kg/hr . - 0.83 mg/mL. - 2 mg in 10 mL Intrathecal. - 4 mg bid. ### Variant angina - Dosing information - Intracoronary： 0.4 mg. - Intracoronary：40-160 mg/day. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Nicardipine contains no information regarding FDA-labeled indications and dosage information for children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nicardipine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nicardipine in pediatric patients. # Contraindications Nicardipine I.V. Injection is contraindicated in patients with advanced aortic stenosis because part of the effect of Nicardipine I.V. Injection is secondary to reduced afterload. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance. Nicardipine is contraindicated in patients with hypersensitivity to the drug. # Warnings ## For Nicardipine capsule ### Increased Angina in Patients With Angina In short-term, placebo-controlled angina trials with Nicardipine (an immediate release oral dosage form of nicardipine), about 7% of patients on Nicardipine (compared with 4% of patients on placebo) have developed increased frequency, duration or severity of angina. Comparisons with beta-blockers also show a greater frequency of increased angina, 4% vs 1%. The mechanism of this effect has not been established. ### Use in Patients With Congestive Heart Failure Although preliminary hemodynamic studies in patients with congestive heart failure have shown that Nicardipine reduced afterload without impairing myocardial contractility, it has a negative inotropic effect in vitro and in some patients. Caution should be exercised when using the drug in congestive heart failure patients, particularly in combination with a beta-blocker. ### Beta-Blocker Withdrawal Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker, preferably over 8 to 10 days. ## PRECAUTIONS ### General Blood Pressure: Because Nicardipine decreases peripheral resistance, careful monitoring of blood pressure during the initial administration and titration of Nicardipine is suggested. Nicardipine, like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is advised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. Use in Patients With Impaired Hepatic Function: Since the liver is the major site of biotransformation and since Nicardipine is subject to first-pass metabolism, Nicardipine should be used with caution in patients having impaired liver function or reduced hepatic blood flow. Patients with severe liver disease developed elevated blood levels (fourfold increase in AUC) and prolonged half-life (19 hours) of Nicardipine. Use in Patients With Impaired Renal Function: When 45-mg Nicardipine bid was given to hypertensive patients with moderate renal impairment, mean AUC and Cmax values were approximately 2-fold to 3-fold higher than in patients with mild renal impairment. Doses in these patients must be adjusted. Mean AUC and Cmax values were similar in patients with mildly impaired renal function and normal volunteers. ## For Nicardipine injection ### Excessive Pharmacodynamic Effects In administering nicardipine, close monitoring of blood pressure and heart rate is required. Nicardipine may occasionally produce symptomatic hypotension or tachycardia. Avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. ## Use in Patients with Angina Increases in frequency, duration, or severity of angina have been seen in chronic therapy with oral nicardipine. Induction or exacerbation of angina has been seen in less than 1% of coronary artery disease patients treated with Nicardipine I.V. The mechanism of this effect has not been established. ### Use in Patients with Heart Failure Titrate slowly when using Nicardipine I.V. Injection, particularly in combination with a beta-blocker, in patients with heart failure or significant left ventricular dysfunction because of possible negative inotropic effects. ### Use in Patients with Impaired Hepatic Function Since nicardipine is metabolized in the liver, consider lower dosages and closely monitor responses in patients with impaired liver function or reduced hepatic blood flow. ### Use in Patients with Impaired Renal Function When Nicardipine I.V. was given to mild to moderate hypertensive patients with moderate renal impairment, a significantly lower systemic clearance and higher area under the curve (AUC) was observed. These results are consistent with those seen after oral administration of nicardipine. Titrate gradually in patients with renal impairment. ### Intravenous Infusion Site To reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, extravasation, and the occurrence of vascular impairment, administer drug through large peripheral veins or central veins rather than arteries or small peripheral veins, such as those on the dorsum of the hand or wrist. To minimize the risk of peripheral venous irritation, change the site of the drug infusion every 12 hours. # Adverse Reactions ## Clinical Trials Experience ## For Nicardipine capsule In multiple-dose US and foreign controlled studies, 667 patients received Nicardipine . In these studies adverse events were elicited by non-directed and in some cases directed questioning; adverse events were generally not serious and about 9% of patients withdrew prematurely from the studies because of them. ### Hypertension The incidence rates of adverse events in hypertensive patients were derived from placebo-controlled clinical trials. Following are the rates of adverse events for Nicardipine (n=322) and placebo (n=140), respectively, that occurred in 0.6% of patients or more on Nicardipine . These represent events considered probably drug related by the investigator. Where the frequency of adverse events for Nicardipine and placebo is similar, causal relationship is uncertain. The only dose-related effect was pedal edema. Uncontrolled experience in over 300 patients with hypertension treated for up to 27.5 months with Nicardipine has shown no unexpected adverse events or increase in incidence of adverse events compared to the controlled clinical trials. ### Rare Events The following rare adverse events have been reported in clinical trials or the literature: Body as a Whole: infection, allergic reaction. Cardiovascular: hypotension, atypical chest pain, peripheral vascular disorder, ventricular extrasystoles, ventricular tachycardia and angina pectoris. Digestive: sore throat, abnormal liver chemistries. Musculoskeletal: arthralgia. Nervous: hot flashes, vertigo, hyperkinesia,impotence, depression, confusion and anxiety. Respiratory: rhinitis and sinusitis. Special Senses: tinnitus, abnormal vision and blurred vision. ### Angina Data are available from only 91 patients with chronic stable angina pectoris who received Nicardipine 30 to 60 mg administered twice daily in open-label clinical trials. Fifty-eight of these patients were treated for at least 30 days. The four most frequently reported adverse events thought by the investigators to be probably related to the use of Nicardipine were vasodilatation (5.5%), pedal edema (4.4%), asthenia (4.4%), and dizziness (3.3%). ## For Nicardipine injection 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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Two hundred forty-four patients participated in two multicenter, double-blind, placebo-controlled trials of Nicardipine I.V. Adverse experiences were generally not serious and most were expected consequences of vasodilation. Adverse experiences occasionally required dosage adjustment. Therapy was discontinued in approximately 12% of patients, mainly due to hypotension, headache, and tachycardia. The table below shows percentage of patients with adverse events where the rate is >3% more common on Nicardipine I.V. than placebo. Other adverse events have been reported in clinical trials or in the literature in association with the use of intravenously administered nicardipine: Body as a Whole: fever, neck pain. Cardiovascular: angina pectoris, atrioventricular block, ST segment depression, inverted T wave and deep-vein thrombophlebitis. Digestive: dyspepsia. Hemic and Lymphatic:thrombocytopenia. Metabolic and Nutritional: hypophosphatemia and peripheral edema. Nervous: confusion and hypertonia Respiratory: respiratory disorder Special Senses: conjunctivitis, ear disorder and tinnitus Urogenital: urinary frequency. Sinus node dysfunction and myocardial infarction, which may be due to disease progression, have been seen in patients on chronic therapy with orally administered nicardipine. ## Postmarketing Experience FDA Package Insert for Abcixmab contains no information regarding Adverse Reactions. # Drug Interactions ## For Nicardipine injection ## Beta-Blockers In most patients, Nicardipine I.V. Injection can safely be used concomitantly with beta blockers. However, titrate slowly when using Nicardipine I.V. Injection in combination with a beta-blocker in heart failure patients. ## Cimetidine Cimetidine has been shown to increase nicardipine plasma concentrations with oral nicardipine administration. Frequently monitor response in patients receiving both drugs. Data with other histamine-2 antagonists are not available. ## Cyclosporine Concomitant administration of oral nicardipine and cyclosporine results in elevated plasma cyclosporine levels. Closely monitor plasma concentrations of cyclosporine during Nicardipine I.V. Injection administration, and reduce the dose of cyclosporine accordingly. ## In Vitro Interaction The plasma protein binding of nicardipine was not altered when therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine, or naproxen were added to human plasma in vitro. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of nicardipine use in pregnant women. However, limited human data in pregnant women with preeclampsia or pre-term labor are available. In animal studies, no embryotoxicity occurred in rats with oral doses 8 times the maximum recommended human dose (MRHD) based on body surface area (mg/m2), but did occur in rabbits with oral doses at 24 times the maximum recommended human dose (MRHD) based on body surface area (mg/m2). Nicardipine I.V. should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Hypotension, reflex tachycardia, postpartum hemorrhage,tocolysis, headache, nausea, dizziness, and flushing have been reported in pregnant women who were treated with intravenous nicardipine for hypertension during pregnancy. Fetal safety results ranged from transient fetal heart rate decelerations to no adverse events. Neonatal safety data ranged from hypotension to no adverse events. Adverse events in women treated with intravenous nicardipine during pre-term labor include pulmonary edema, dyspnea, hypoxia, hypotension, tachycardia, headache, and phlebitis at site of injection. Neonatal adverse events include acidosis (pH<7.25). In embryofetal toxicity studies, nicardipine was administered intravenously to pregnant rats and rabbits during organogenesis at doses up to 0.14 times the MRHD based on body surface area (mg/m2) (5 mg/kg/day) (rats) and 0.03 times the MRHD based on body surface area (mg/m2) (0.5 mg/kg/day) (rabbits). No embryotoxicity or teratogenicity was seen at these doses. Embryotoxicity, but no teratogenicity was seen at 0.27 times the MRHD based on body surface area (mg/m2) (10 mg/kg/day) in rats and at 0.05 times the MRHD based on body surface are (mg/m2) (1 mg/kg/day) in rabbits. In other animal studies, pregnant Japanese White rabbits received oral nicardipine during organogenesis, at doses 8 and 24 times the MRHD based on body surface area (mg/m2) (50 and 150 mg/kg/day). Embryotoxicity occurred at the high dose along with signs of maternal toxicity (marked maternal weight gain suppression). New Zealand albino rabbits received oral nicardipine during organogenesis, at doses up to 16 times the MRHD based on body surface area (mg/m2) (100 mg nicardipine/kg/day). While significant maternal mortality occurred, no adverse effects on the fetus were observed. Pregnant rats received oral nicardipine from day 6 through day 15 of gestation at doses up to 8 times the MRHD based on body surface area (mg/m2) (100 mg/kg/day). There was no evidence of embryotoxicity or teratogenicity; however, dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nicardipine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nicardipine during labor and delivery. ### Nursing Mothers Nicardipine is minimally excreted into human milk. Among 18 infants exposed to nicardipine through breast milk in the postpartum period, calculated daily infant dose was less than 0.3 mcg and there were no adverse events observed. Consider the possibility of infant exposure when using nicardipine in nursing mothers. In a study of 11 women who received oral nicardipine 4 to 14 days postpartum, 4 women received immediate-release nicardipine 40 to 80 mg daily, 6 received sustained-release nicardipine 100 to 150 mg daily, and one received intravenous nicardipine 120 mg daily. The peak milk concentration was 7.3 mcg/L (range 1.9-18.8), and the mean milk concentration was 4.4 mcg/L (range 1.3-13.8). Infants received an average of 0.073% of the weight-adjusted maternal oral dose and 0.14% of the weight-adjusted maternal intravenous dose. In another study of seven women who received intravenous nicardipine for an average of 1.9 days in the immediate postpartum period as therapy for pre-eclampsia, 34 milk samples were obtained at unspecified times and nicardipine was undetectable (<5 mcg/L) in 82% of the samples. Four women who received 1 to 6.5 mg/hour of nicardipine had 6 milk samples with detectable nicardipine levels (range 5.1 to 18.5 mcg/L). The highest concentration of 18.5 mcg/L was found in a woman who received 5.5 mg/hour of nicardipine. The estimated maximum dose in a breastfed infant was < 0.3 mcg daily or between 0.015 to 0.004% of the therapeutic dose in a 1 kg infant. ### Pediatric Use Safety and efficacy in patients under the age of 18 have not been established. ### Geriatic Use The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (>65 years) and young healthy adults. Clinical studies of nicardipine 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, use low initial doses in elderly patients, 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 Nicardipine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nicardipine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nicardipine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nicardipine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nicardipine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nicardipine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral and intravenous ## Instructions for Administration Administer Nicardipine I.V. by a central line or through a large peripheral vein. Change the infusion site every 12 hours if administered via peripheral vein. Nicardipine I.V. Injection is available as a single-use, ready-to-use, iso-osmotic solution for intravenous administration. No further dilution is required. Inspect Nicardipine I.V. Injection visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check the container for minute leaks prior to use by squeezing the bag firmly; ensure that the seal is intact. If leaks are found, discard solution as sterility may be impaired. Nicardipine I.V. Injection is normally a clear, colorless to yellow solution. Do not combine Nicardipine I.V. Injection with any product in the same intravenous line or container. Do not add supplementary medication to the bag. Protect from light until ready to use. Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete. ## Preparation for administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. ### Monitoring The time course of blood pressure decrease is dependent on the initial rate of infusion and the frequency of dosage adjustment. With constant infusion, blood pressure begins to fall within minutes. It reaches about 50% of its ultimate decrease in about 45 minutes. Monitor blood pressure and heart rate continually during infusion and avoid too rapid or excessive blood pressure drop during treatment. If there is concern of impending hypotension or tachycardia, the infusion should be discontinued. Then, when blood pressure has stabilized, infusion of Nicardipine I.V. Injection may be restarted at low doses such as 15‑25 mL/hr (3.0 - 5.0 mg/hr) and adjusted to maintain desired blood pressure. # IV Compatibility FDA Package Insert for Nicardipine contains no information regarding IV compatibility. # Overdosage ## For Nicardipine capsule Three overdosages with Nicardipine or Nicardipine have been reported. Two occurred in adults, 1 of whom ingested 600 mg of Nicardipine and the other 2160 mg of Nicardipine . Symptoms included marked hypotension,bradycardia, palpitations, flushing, drowsiness, confusion, and slurred speech. All symptoms resolved without sequelae. The third over-dosage occurred in a 1-year-old child who ingested half of the powder in a 30-mg Nicardipine capsule. The child remained asymptomatic. Based on results obtained in laboratory animals, overdosage may cause systemic hypotension, bradycardia (following initial tachycardia) and progressive atrioventricular conduction block. Reversible hepatic function abnormalities and sporadic focal hepatic necrosis were noted in some animal species receiving very large doses of nicardipine. For treatment of overdose standard measures (for example, evacuation of gastric contents, elevation of extremities, attention to circulating fluid volume, and urine output) including monitoring of cardiac and respiratory functions should be implemented. The patient should be positioned so as to avoid cerebral anoxia. Frequent blood pressure determinations are essential. Vasopressors are clinically indicated for patients exhibiting profound hypotension. Intravenous calcium gluconate may help reverse the effects of calcium entry blockade. ## For Nicardipine Injection Several overdosages with orally administered nicardipine have been reported. One adult patient allegedly ingested 600 mg of immediate-release oral nicardipine, and another patient, 2160 mg of the sustained-release formulation of nicardipine. Symptoms included marked hypotension, bradycardia, palpitations, flushing, drowsiness, confusion and slurred speech. All symptoms resolved without sequelae. An overdosage occurred in a one year old child who ingested half of the powder in a 30 mg nicardipine standard capsule. The child remained asymptomatic. Based on results obtained in laboratory animals, lethal overdose may cause systemic hypotension, bradycardia (following initial tachycardia) and progressive atrioventricular conduction block. Reversible hepatic function abnormalities and sporadic focal hepatic necrosis were noted in some animal species receiving very large doses of nicardipine. For treatment of overdosage, implement standard measures including monitoring of cardiac and respiratory functions. Position the patient so as to avoid cerebral anoxia. Use vasopressors for patients exhibiting profound hypotension. # Pharmacology ## Mechanism of Action Nicardipine inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle without changing serum calcium concentrations. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. The effects of nicardipine are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine produced relaxation of coronary vascular smooth muscle at drug levels which cause little or no negative inotropic effect. ## Structure Cardene (nicardipine hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker). Nicardipine I.V. Injection for intravenous administration contains 40 mg of nicardipine hydrochloride per 200 mL (0.2 mg/mL) in either dextrose or sodium chloride. Nicardipine hydrochloride is a dihydropyridine derivative with IUPAC (International Union of Pure and Applied Chemistry) chemical name (±)-2-(benzyl-methyl amino) ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride and has the following structure: Nicardipine hydrochloride is a greenish-yellow, odorless, crystalline powder that melts at about 169°C. It is freely soluble in chloroform, methanol, and glacial acetic acid, sparingly soluble in anhydrous ethanol, slightly soluble in n-butanol, water, 0.01 M potassium dihydrogen phosphate, acetone, and dioxane, very slightly soluble in ethyl acetate, and practically insoluble in benzene, ether, and hexane. It has a molecular weight of 515.99. ## Pharmacodynamics ### Hemodynamics Nicardipine I.V. produces significant decreases in systemic vascular resistance. In a study of intra-arterially administered Nicardipine I.V., the degree of vasodilation and the resultant decrease in blood pressure were more prominent in hypertensive patients than in normotensive volunteers. Administration of Nicardipine I.V. to normotensive volunteers at dosages of 0.25 to 3.0 mg/hr for eight hours produced changes of <5 mmHg in systolic blood pressure and <3 mmHg in diastolic blood pressure. An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced. In placebo-controlled trials, the mean increases in heart rate were 7 ± 1 bpm in postoperative patients and 8 ± 1 bpm in patients with severe hypertension at the end of the maintenance period. Hemodynamic studies following intravenous dosing in patients with coronary artery disease and normal or moderately abnormal left ventricular function have shown significant increases in ejection fraction and cardiac output with no significant change, or a small decrease, in left ventricular end-diastolic pressure (LVEDP). There is evidence that Nicardipine increases blood flow. Coronary dilatation induced by Nicardipine I.V. improves perfusion and aerobic metabolism in areas with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption. In patients with coronary artery disease, Nicardipine I.V., administered after beta-blockade, significantly improved systolic and diastolic left ventricular function. In congestive heart failure patients with impaired left ventricular function, Nicardipine I.V. increased cardiac output both at rest and during exercise. Decreases in left ventricular end-diastolic pressure were also observed. However, in some patients with severe left ventricular dysfunction, it may have a negative inotropic effect and could lead to worsened failure. “Coronary steal” has not been observed during treatment with Nicardipine I.V. (Coronary steal is the detrimental redistribution of coronary blood flow in patients with coronary artery disease from underperfused areas toward better perfused areas.) Nicardipine I.V. has been shown to improve systolic shortening in both normal and hypokinetic segments of myocardial muscle. Radionuclide angiography has confirmed that wall motion remained improved during increased oxygen demand. (Occasional patients have developed increased angina upon receiving oral nicardipine. Whether this represents coronary steal in these patients, or is the result of increased heart rate and decreased diastolic pressure, is not clear.) In patients with coronary artery disease, Nicardipine I.V. improves left ventricular diastolic distensibility during the early filling phase, probably due to a faster rate of myocardial relaxation in previously underperfused areas. There is little or no effect on normal myocardium, suggesting the improvement is mainly by indirect mechanisms such as afterload reduction and reduced ischemia. Nicardipine I.V. has no negative effect on myocardial relaxation at therapeutic doses. The clinical benefits of these properties have not yet been demonstrated. ### Electrophysiologic Effects In general, no detrimental effects on the cardiac conduction system have been seen with Nicardipine I.V. During acute electrophysiologic studies, it increased heart rate and prolonged the corrected QT interval to a minor degree. It did not affect sinus node recovery or SA conduction times. The PA, AH, and HV intervals- or the functional and effective refractory periods of the atrium were not prolonged. The relative and effective refractory periods of the His-Purkinje system were slightly shortened. - PA = conduction time from high to low right atrium; AH = conduction time from low right atrium to His bundle deflection, or AV nodal conduction time; HV = conduction time through the His bundle and the bundle branch-Purkinje system. ## Hepatic Function Because the liver extensively metabolizes nicardipine, plasma concentrations are influenced by changes in hepatic function. In a clinical study with oral nicardipine in patients with severe liver disease, plasma concentrations were elevated and the half-life was prolonged. Similar results were obtained in patients with hepatic disease when Nicardipine I.V. (nicardipine hydrochloride) was administered for 24 hours at 0.6 mg/hr. ## Renal Function When Nicardipine I.V. was given to mild to moderate hypertensive patients with moderate degrees of renal impairment, significant reduction in glomerular filtration rate (GFR) and effective renal plasma flow (RPF) was observed. No significant differences in liver blood flow were observed in these patients. A significantly lower systemic clearance and higher area under the curve (AUC) were observed. When oral nicardipine (20 mg or 30 mg TID) was given to hypertensive patients with impaired renal function, mean plasma concentrations, AUC, and Cmaxwere approximately two-fold higher than in healthy controls. There is a transient increase in electrolyte excretion, including sodium. Acute bolus administration of Nicardipine I.V. (2.5 mg) in healthy volunteers decreased mean arterial pressure and renal vascular resistance; glomerular filtration rate (GFR), renal plasma flow (RPF), and the filtration fraction were unchanged. In healthy patients undergoing abdominal surgery, Nicardipine I.V. (10 mg over 20 minutes) increased GFR with no change in RPF when compared with placebo. In hypertensive type II diabetic patients with nephropathy, oral nicardipine (20 mg TID) did not change RPF and GFR, but reduced renal vascular resistance. ## Pulmonary Function In two well-controlled studies of patients with obstructive airway disease treated with oral nicardipine, no evidence of increased bronchospasm was seen. In one of the studies, oral nicardipine improved forced expiratory volume 1 second (FEV1) and forced vital capacity (FVC) in comparison with metoprolol. Adverse experiences reported in a limited number of patients with asthma, reactive airway disease, or obstructive airway disease are similar to all patients treated with oral nicardipine. ## Pharmacokinetics ### Distribution Rapid dose-related increases in nicardipine plasma concentrations are seen during the first two hours after the start of an infusion of Nicardipine I.V. Plasma concentrations increase at a much slower rate after the first few hours, and approach steady state at 24 to 48 hours. The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (>65 years) and young healthy adults. On termination of the infusion, nicardipine concentrations decrease rapidly, with at least a 50% decrease during the first two hours post-infusion. The effects of nicardipine on blood pressure significantly correlate with plasma concentrations. Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range. Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase (α-half-life of 2.7 minutes), an intermediate phase (β-half-life of 44.8 minutes), and a slow terminal phase (γ-half-life of 14.4 hours) that can only be detected after long-term infusions. Total plasma clearance (Cl) is 0.4 L/hrkg, and the apparent volume of distribution (Vd) using a non-compartment model is 8.3 L/kg. The pharmacokinetics of Nicardipine I.V. are linear over the dosage range of 0.5 to 40.0 mg/hr. ## Metabolism and Excretion Nicardipine I.V. has been shown to be rapidly and extensively metabolized by the liver. Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes. After coadministration of a radioactive intravenous dose of Nicardipine I.V. with an oral 30 mg dose given every 8 hours, 49% of the radioactivity was recovered in the urine and 43% in the feces within 96 hours. None of the dose was recovered as unchanged nicardipine. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility Rats treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of 5, 15, or 45 mg/kg/day) for two years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and three-month studies in the rat have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine (T4) levels with a consequent increase in plasma levels of thyroid stimulating hormone (TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid. In rats on an iodine deficient diet, nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementation. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100 mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes. There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for one year and no evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man. There was no evidence of a mutagenic potential of nicardipine in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters. No impairment of fertility was seen in male or female rats administered nicardipine at oral doses as high as 100 mg/kg/day (human equivalent dose about 16 mg/kg/day, 8 times the maximum recommended oral dose). ## Reproductive and Developmental Toxicology Embryotoxicity, but no teratogenicity, was seen at intravenous doses of 10 mg nicardipine/kg/day in rats and 1 mg/kg/day in rabbits. These doses in the rat and rabbit are equivalent to human IV doses of about 1.6 mg/kg/day and 0.32 mg/kg/day respectively. (The total daily human dose delivered by a continuous IV infusion ranges from 1.2 to 6 mg/kg/day, depending on duration at different infusion rates ranging from 3 to 15 mg/hr as individual patients are titrated for optimal results.) Nicardipine was also embryotoxic when administered orally to pregnant Japanese White rabbits, during organogenesis, at 150 mg/kg/day (a dose associated with marked body weight gain suppression in the treated doe), but not at 50 mg/kg/day (human equivalent dose about 16 mg/kg/day or about 8 times the maximum recommended human oral dose). No adverse effects on the fetus were observed when New Zealand albino rabbits were treated orally, during organogenesis, with up to 100 mg nicardipine/kg/day (a dose associated with significant mortality in the treated doe). In pregnant rats administered nicardipine orally at doses of up to 100 mg/kg/day (human equivalent dose about 16 mg/kg/day) there was no evidence of embryotoxicity or teratogenicity. However, dystocia, reduced birth weight, reduced neonatal survival and reduced neonatal weight gain were noted. # Clinical Studies ## Effects In Hypertension In patients with mild to moderate chronic stable essential hypertension, Nicardipine I.V. (0.5 to 4.0 mg/hr) produced dose-dependent decreases in blood pressure. At the end of a 48-hour infusion at 4.0 mg/hr, the decreases were 26.0 mmHg (17%) in systolic blood pressure and 20.7 mmHg (20%) in diastolic blood pressure. In other settings (e.g., patients with severe or postoperative hypertension), Nicardipine I.V. (5 to 15 mg/hr) produced dose-dependent decreases in blood pressure. Higher infusion rates produced therapeutic responses more rapidly. The mean time to therapeutic response for severe hypertension, defined as diastolic blood pressure ≤95 mmHg or ≥25 mmHg decrease and systolic blood pressure ≤160 mmHg, was 77 ± 5.2 minutes. The average maintenance dose was 8.0 mg/hr. The mean time to therapeutic response for postoperative hypertension, defined as ≥15% reduction in diastolic or systolic blood pressure, was 11.5 ± 0.8 minutes. The average maintenance dose was 3.0 mg/hr.Deep vein thrombosis # How Supplied ## For Nicardipine capsule Nicardipine hydrochloride capsules are available containing 20 mg or 30 mg of nicardipine hydrochloride, USP. The 20 mg capsule is a hard-shell gelatin capsule with a medium blue-green opaque cap and an ivory opaque body axially imprinted with MYLAN over 1020 in black ink on both the cap and the body. They are available as follows: NDC 0378-1020-77 bottles of 90 capsules NDC 0378-1020-05 bottles of 500 capsules The 30 mg capsule is a hard-shell gelatin capsule with a bluish green opaque cap and a rich yellow opaque body axially imprinted with MYLAN over 1430 in black ink on both the cap and the body. They are available as follows: NDC 0378-1430-77 bottles of 90 capsules NDC 0378-1430-05 bottles of 500 capsules ## For Nicardipine Injection Nicardipine I.V. Injection is supplied as a single-use, ready-to-use, iso-osmotic solution for intravenous administration in a 200 mL GALAXY container with 40 mg (0.2 mg/mL) nicardipine hydrochloride in either dextrose or sodium chloride. ## Storage ## For Nicardipine capsule Store at 20° to 25°C (68° to 77°F). Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. ## For Nicardipine Injection Store at controlled room temperature 20° to 25°C (68° to 77°F), refer to USP Controlled Room Temperature. Protect from freezing. Avoid excessive heat. Protect from light, store in carton until ready to use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Nicardipine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Nicardipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cardene - Cardene IV - Cardene SR # Look-Alike Drug Names Nicardipine - Nifedipine Nicardipine - Nimodipine # Drug Shortage Status # Price	Nicardipine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Turky Alkathery, M.D. [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 Nicardipine is a Calcium Channel Blocker that is FDA approved for the treatment of short-term treatment of hypertension when oral therapy is not feasible or not desirable. Common adverse reactions include Hypotension, Peripheral edema, Tachyarrhythmia, Nausea, Vomiting, Headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - Dosing information (capsule) - The dose of nicardipine hydrochloride should be individually adjusted according to the blood pressure response. - Initial dosage: 20 mg PO tid. - Dosage range: 20 mg - 40 mg PO tid. The maximum blood pressure lowering effect occurs approximately 1 to 2 hours after dosing. To assess the adequacy of blood pressure response, the blood pressure should be measured at trough (8 hours after dosing). Because of the prominent peak effects of nicardipine, blood pressure should be measured 1 to 2 hours after dosing, particularly during initiation of therapy. - At least 3 days should be allowed before increasing the nicardipine dose to ensure achievement of steady-state plasma drug concentrations. - Dosing information (Injection) - Dosage as a Substitute for Oral Nicardipine Therapy - The intravenous infusion rate required to produce an average plasma concentration equivalent to a given oral dose at steady state is shown in the following table: - Dosage for Initiation of Therapy in a Patient Not Receiving Oral Nicardipine - Initiate dosage: 25 mL/hr (5.0 mg/hr). - If desired blood pressure reduction is not achieved at this dose, the infusion rate may be increased by 12.5 mL/hr (2.5 mg/hr) every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 75 mL/hr (15.0 mg/hr), until desired blood pressure reduction is achieved. - Following achievement of the blood pressure goal utilizing rapid titration, decrease the infusion rate to 15 mL/hr (3 mg/hr). - Drug Discontinuation and Transition to an Oral Antihypertensive Agent - Discontinuation of infusion is followed by a 50% offset of action in about 30 minutes. - If treatment includes transfer to an oral antihypertensive agent other than oral nicardipine, initiate therapy upon discontinuation of Nicardipine I.V.Injection. - If oral nicardipine is to be used, administer the first dose 1 hour prior to discontinuation of the infusion. - Special Populations - Titrate Nicardipine I.V. Injection slowly in patients with heart failure or impaired hepatic or renal function. ### Angina - Dosing information (Capsule only) - Initial dosage: 20 mg PO tid. - Dosage range: 20 mg to 40 mg PO tid. At least 3 days should be allowed before increasing the nicardipine hydrochloride dose to ensure achievement of steady-state plasma drug concentrations. - Concomitant Use With Other Antianginal Agents ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nicardipine in adult patients. ### Non–Guideline-Supported Use ### Electroconvulsive therapy - Dosing information - Not applicable [1] ### Migraine - Dosing information - 20 mg PO tid.[2] - 20 mg PO bid.[3] ### Subarachnoid hemorrhage - Vasospasm - Dosing information - 0.15 mg/kg/hr .[4] - 0.83 mg/mL.[5] - 2 mg in 10 mL Intrathecal.[6] - 4 mg bid.[7] ### Variant angina - Dosing information - Intracoronary： 0.4 mg.[8] - Intracoronary：40-160 mg/day. [9] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Nicardipine contains no information regarding FDA-labeled indications and dosage information for children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Nicardipine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Nicardipine in pediatric patients. # Contraindications Nicardipine I.V. Injection is contraindicated in patients with advanced aortic stenosis because part of the effect of Nicardipine I.V. Injection is secondary to reduced afterload. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance. Nicardipine is contraindicated in patients with hypersensitivity to the drug. # Warnings ## For Nicardipine capsule ### Increased Angina in Patients With Angina In short-term, placebo-controlled angina trials with Nicardipine (an immediate release oral dosage form of nicardipine), about 7% of patients on Nicardipine (compared with 4% of patients on placebo) have developed increased frequency, duration or severity of angina. Comparisons with beta-blockers also show a greater frequency of increased angina, 4% vs 1%. The mechanism of this effect has not been established. ### Use in Patients With Congestive Heart Failure Although preliminary hemodynamic studies in patients with congestive heart failure have shown that Nicardipine reduced afterload without impairing myocardial contractility, it has a negative inotropic effect in vitro and in some patients. Caution should be exercised when using the drug in congestive heart failure patients, particularly in combination with a beta-blocker. ### Beta-Blocker Withdrawal Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker, preferably over 8 to 10 days. ## PRECAUTIONS ### General Blood Pressure: Because Nicardipine decreases peripheral resistance, careful monitoring of blood pressure during the initial administration and titration of Nicardipine is suggested. Nicardipine, like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is advised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. Use in Patients With Impaired Hepatic Function: Since the liver is the major site of biotransformation and since Nicardipine is subject to first-pass metabolism, Nicardipine should be used with caution in patients having impaired liver function or reduced hepatic blood flow. Patients with severe liver disease developed elevated blood levels (fourfold increase in AUC) and prolonged half-life (19 hours) of Nicardipine. Use in Patients With Impaired Renal Function: When 45-mg Nicardipine bid was given to hypertensive patients with moderate renal impairment, mean AUC and Cmax values were approximately 2-fold to 3-fold higher than in patients with mild renal impairment. Doses in these patients must be adjusted. Mean AUC and Cmax values were similar in patients with mildly impaired renal function and normal volunteers. ## For Nicardipine injection ### Excessive Pharmacodynamic Effects In administering nicardipine, close monitoring of blood pressure and heart rate is required. Nicardipine may occasionally produce symptomatic hypotension or tachycardia. Avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage. ## Use in Patients with Angina Increases in frequency, duration, or severity of angina have been seen in chronic therapy with oral nicardipine. Induction or exacerbation of angina has been seen in less than 1% of coronary artery disease patients treated with Nicardipine I.V. The mechanism of this effect has not been established. ### Use in Patients with Heart Failure Titrate slowly when using Nicardipine I.V. Injection, particularly in combination with a beta-blocker, in patients with heart failure or significant left ventricular dysfunction because of possible negative inotropic effects. ### Use in Patients with Impaired Hepatic Function Since nicardipine is metabolized in the liver, consider lower dosages and closely monitor responses in patients with impaired liver function or reduced hepatic blood flow. ### Use in Patients with Impaired Renal Function When Nicardipine I.V. was given to mild to moderate hypertensive patients with moderate renal impairment, a significantly lower systemic clearance and higher area under the curve (AUC) was observed. These results are consistent with those seen after oral administration of nicardipine. Titrate gradually in patients with renal impairment. ### Intravenous Infusion Site To reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, extravasation, and the occurrence of vascular impairment, administer drug through large peripheral veins or central veins rather than arteries or small peripheral veins, such as those on the dorsum of the hand or wrist. To minimize the risk of peripheral venous irritation, change the site of the drug infusion every 12 hours. # Adverse Reactions ## Clinical Trials Experience ## For Nicardipine capsule In multiple-dose US and foreign controlled studies, 667 patients received Nicardipine . In these studies adverse events were elicited by non-directed and in some cases directed questioning; adverse events were generally not serious and about 9% of patients withdrew prematurely from the studies because of them. ### Hypertension The incidence rates of adverse events in hypertensive patients were derived from placebo-controlled clinical trials. Following are the rates of adverse events for Nicardipine (n=322) and placebo (n=140), respectively, that occurred in 0.6% of patients or more on Nicardipine . These represent events considered probably drug related by the investigator. Where the frequency of adverse events for Nicardipine and placebo is similar, causal relationship is uncertain. The only dose-related effect was pedal edema. Uncontrolled experience in over 300 patients with hypertension treated for up to 27.5 months with Nicardipine has shown no unexpected adverse events or increase in incidence of adverse events compared to the controlled clinical trials. ### Rare Events The following rare adverse events have been reported in clinical trials or the literature: Body as a Whole: infection, allergic reaction. Cardiovascular: hypotension, atypical chest pain, peripheral vascular disorder, ventricular extrasystoles, ventricular tachycardia and angina pectoris. Digestive: sore throat, abnormal liver chemistries. Musculoskeletal: arthralgia. Nervous: hot flashes, vertigo, hyperkinesia,impotence, depression, confusion and anxiety. Respiratory: rhinitis and sinusitis. Special Senses: tinnitus, abnormal vision and blurred vision. ### Angina Data are available from only 91 patients with chronic stable angina pectoris who received Nicardipine 30 to 60 mg administered twice daily in open-label clinical trials. Fifty-eight of these patients were treated for at least 30 days. The four most frequently reported adverse events thought by the investigators to be probably related to the use of Nicardipine were vasodilatation (5.5%), pedal edema (4.4%), asthenia (4.4%), and dizziness (3.3%). ## For Nicardipine injection 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 adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Two hundred forty-four patients participated in two multicenter, double-blind, placebo-controlled trials of Nicardipine I.V. Adverse experiences were generally not serious and most were expected consequences of vasodilation. Adverse experiences occasionally required dosage adjustment. Therapy was discontinued in approximately 12% of patients, mainly due to hypotension, headache, and tachycardia. The table below shows percentage of patients with adverse events where the rate is >3% more common on Nicardipine I.V. than placebo. Other adverse events have been reported in clinical trials or in the literature in association with the use of intravenously administered nicardipine: Body as a Whole: fever, neck pain. Cardiovascular: angina pectoris, atrioventricular block, ST segment depression, inverted T wave and deep-vein thrombophlebitis. Digestive: dyspepsia. Hemic and Lymphatic:thrombocytopenia. Metabolic and Nutritional: hypophosphatemia and peripheral edema. Nervous: confusion and hypertonia Respiratory: respiratory disorder Special Senses: conjunctivitis, ear disorder and tinnitus Urogenital: urinary frequency. Sinus node dysfunction and myocardial infarction, which may be due to disease progression, have been seen in patients on chronic therapy with orally administered nicardipine. ## Postmarketing Experience FDA Package Insert for Abcixmab contains no information regarding Adverse Reactions. # Drug Interactions ## For Nicardipine injection ## Beta-Blockers In most patients, Nicardipine I.V. Injection can safely be used concomitantly with beta blockers. However, titrate slowly when using Nicardipine I.V. Injection in combination with a beta-blocker in heart failure patients. ## Cimetidine Cimetidine has been shown to increase nicardipine plasma concentrations with oral nicardipine administration. Frequently monitor response in patients receiving both drugs. Data with other histamine-2 antagonists are not available. ## Cyclosporine Concomitant administration of oral nicardipine and cyclosporine results in elevated plasma cyclosporine levels. Closely monitor plasma concentrations of cyclosporine during Nicardipine I.V. Injection administration, and reduce the dose of cyclosporine accordingly. ## In Vitro Interaction The plasma protein binding of nicardipine was not altered when therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine, or naproxen were added to human plasma in vitro. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of nicardipine use in pregnant women. However, limited human data in pregnant women with preeclampsia or pre-term labor are available. In animal studies, no embryotoxicity occurred in rats with oral doses 8 times the maximum recommended human dose (MRHD) based on body surface area (mg/m2), but did occur in rabbits with oral doses at 24 times the maximum recommended human dose (MRHD) based on body surface area (mg/m2). Nicardipine I.V. should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Hypotension, reflex tachycardia, postpartum hemorrhage,tocolysis, headache, nausea, dizziness, and flushing have been reported in pregnant women who were treated with intravenous nicardipine for hypertension during pregnancy. Fetal safety results ranged from transient fetal heart rate decelerations to no adverse events. Neonatal safety data ranged from hypotension to no adverse events. Adverse events in women treated with intravenous nicardipine during pre-term labor include pulmonary edema, dyspnea, hypoxia, hypotension, tachycardia, headache, and phlebitis at site of injection. Neonatal adverse events include acidosis (pH<7.25). In embryofetal toxicity studies, nicardipine was administered intravenously to pregnant rats and rabbits during organogenesis at doses up to 0.14 times the MRHD based on body surface area (mg/m2) (5 mg/kg/day) (rats) and 0.03 times the MRHD based on body surface area (mg/m2) (0.5 mg/kg/day) (rabbits). No embryotoxicity or teratogenicity was seen at these doses. Embryotoxicity, but no teratogenicity was seen at 0.27 times the MRHD based on body surface area (mg/m2) (10 mg/kg/day) in rats and at 0.05 times the MRHD based on body surface are (mg/m2) (1 mg/kg/day) in rabbits. In other animal studies, pregnant Japanese White rabbits received oral nicardipine during organogenesis, at doses 8 and 24 times the MRHD based on body surface area (mg/m2) (50 and 150 mg/kg/day). Embryotoxicity occurred at the high dose along with signs of maternal toxicity (marked maternal weight gain suppression). New Zealand albino rabbits received oral nicardipine during organogenesis, at doses up to 16 times the MRHD based on body surface area (mg/m2) (100 mg nicardipine/kg/day). While significant maternal mortality occurred, no adverse effects on the fetus were observed. Pregnant rats received oral nicardipine from day 6 through day 15 of gestation at doses up to 8 times the MRHD based on body surface area (mg/m2) (100 mg/kg/day). There was no evidence of embryotoxicity or teratogenicity; however, dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nicardipine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Nicardipine during labor and delivery. ### Nursing Mothers Nicardipine is minimally excreted into human milk. Among 18 infants exposed to nicardipine through breast milk in the postpartum period, calculated daily infant dose was less than 0.3 mcg and there were no adverse events observed. Consider the possibility of infant exposure when using nicardipine in nursing mothers. In a study of 11 women who received oral nicardipine 4 to 14 days postpartum, 4 women received immediate-release nicardipine 40 to 80 mg daily, 6 received sustained-release nicardipine 100 to 150 mg daily, and one received intravenous nicardipine 120 mg daily. The peak milk concentration was 7.3 mcg/L (range 1.9-18.8), and the mean milk concentration was 4.4 mcg/L (range 1.3-13.8). Infants received an average of 0.073% of the weight-adjusted maternal oral dose and 0.14% of the weight-adjusted maternal intravenous dose. In another study of seven women who received intravenous nicardipine for an average of 1.9 days in the immediate postpartum period as therapy for pre-eclampsia, 34 milk samples were obtained at unspecified times and nicardipine was undetectable (<5 mcg/L) in 82% of the samples. Four women who received 1 to 6.5 mg/hour of nicardipine had 6 milk samples with detectable nicardipine levels (range 5.1 to 18.5 mcg/L). The highest concentration of 18.5 mcg/L was found in a woman who received 5.5 mg/hour of nicardipine. The estimated maximum dose in a breastfed infant was < 0.3 mcg daily or between 0.015 to 0.004% of the therapeutic dose in a 1 kg infant. ### Pediatric Use Safety and efficacy in patients under the age of 18 have not been established. ### Geriatic Use The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (>65 years) and young healthy adults. Clinical studies of nicardipine 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, use low initial doses in elderly patients, 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 Nicardipine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nicardipine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nicardipine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nicardipine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nicardipine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nicardipine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral and intravenous ## Instructions for Administration Administer Nicardipine I.V. by a central line or through a large peripheral vein. Change the infusion site every 12 hours if administered via peripheral vein. Nicardipine I.V. Injection is available as a single-use, ready-to-use, iso-osmotic solution for intravenous administration. No further dilution is required. Inspect Nicardipine I.V. Injection visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check the container for minute leaks prior to use by squeezing the bag firmly; ensure that the seal is intact. If leaks are found, discard solution as sterility may be impaired. Nicardipine I.V. Injection is normally a clear, colorless to yellow solution. Do not combine Nicardipine I.V. Injection with any product in the same intravenous line or container. Do not add supplementary medication to the bag. Protect from light until ready to use. Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is complete. ## Preparation for administration 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. ### Monitoring The time course of blood pressure decrease is dependent on the initial rate of infusion and the frequency of dosage adjustment. With constant infusion, blood pressure begins to fall within minutes. It reaches about 50% of its ultimate decrease in about 45 minutes. Monitor blood pressure and heart rate continually during infusion and avoid too rapid or excessive blood pressure drop during treatment. If there is concern of impending hypotension or tachycardia, the infusion should be discontinued. Then, when blood pressure has stabilized, infusion of Nicardipine I.V. Injection may be restarted at low doses such as 15‑25 mL/hr (3.0 - 5.0 mg/hr) and adjusted to maintain desired blood pressure. # IV Compatibility FDA Package Insert for Nicardipine contains no information regarding IV compatibility. # Overdosage ## For Nicardipine capsule Three overdosages with Nicardipine or Nicardipine have been reported. Two occurred in adults, 1 of whom ingested 600 mg of Nicardipine and the other 2160 mg of Nicardipine . Symptoms included marked hypotension,bradycardia, palpitations, flushing, drowsiness, confusion, and slurred speech. All symptoms resolved without sequelae. The third over-dosage occurred in a 1-year-old child who ingested half of the powder in a 30-mg Nicardipine capsule. The child remained asymptomatic. Based on results obtained in laboratory animals, overdosage may cause systemic hypotension, bradycardia (following initial tachycardia) and progressive atrioventricular conduction block. Reversible hepatic function abnormalities and sporadic focal hepatic necrosis were noted in some animal species receiving very large doses of nicardipine. For treatment of overdose standard measures (for example, evacuation of gastric contents, elevation of extremities, attention to circulating fluid volume, and urine output) including monitoring of cardiac and respiratory functions should be implemented. The patient should be positioned so as to avoid cerebral anoxia. Frequent blood pressure determinations are essential. Vasopressors are clinically indicated for patients exhibiting profound hypotension. Intravenous calcium gluconate may help reverse the effects of calcium entry blockade. ## For Nicardipine Injection Several overdosages with orally administered nicardipine have been reported. One adult patient allegedly ingested 600 mg of immediate-release oral nicardipine, and another patient, 2160 mg of the sustained-release formulation of nicardipine. Symptoms included marked hypotension, bradycardia, palpitations, flushing, drowsiness, confusion and slurred speech. All symptoms resolved without sequelae. An overdosage occurred in a one year old child who ingested half of the powder in a 30 mg nicardipine standard capsule. The child remained asymptomatic. Based on results obtained in laboratory animals, lethal overdose may cause systemic hypotension, bradycardia (following initial tachycardia) and progressive atrioventricular conduction block. Reversible hepatic function abnormalities and sporadic focal hepatic necrosis were noted in some animal species receiving very large doses of nicardipine. For treatment of overdosage, implement standard measures including monitoring of cardiac and respiratory functions. Position the patient so as to avoid cerebral anoxia. Use vasopressors for patients exhibiting profound hypotension. # Pharmacology ## Mechanism of Action Nicardipine inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle without changing serum calcium concentrations. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. The effects of nicardipine are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine produced relaxation of coronary vascular smooth muscle at drug levels which cause little or no negative inotropic effect. ## Structure Cardene (nicardipine hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker). Nicardipine I.V. Injection for intravenous administration contains 40 mg of nicardipine hydrochloride per 200 mL (0.2 mg/mL) in either dextrose or sodium chloride. Nicardipine hydrochloride is a dihydropyridine derivative with IUPAC (International Union of Pure and Applied Chemistry) chemical name (±)-2-(benzyl-methyl amino) ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride and has the following structure: Nicardipine hydrochloride is a greenish-yellow, odorless, crystalline powder that melts at about 169°C. It is freely soluble in chloroform, methanol, and glacial acetic acid, sparingly soluble in anhydrous ethanol, slightly soluble in n-butanol, water, 0.01 M potassium dihydrogen phosphate, acetone, and dioxane, very slightly soluble in ethyl acetate, and practically insoluble in benzene, ether, and hexane. It has a molecular weight of 515.99. ## Pharmacodynamics ### Hemodynamics Nicardipine I.V. produces significant decreases in systemic vascular resistance. In a study of intra-arterially administered Nicardipine I.V., the degree of vasodilation and the resultant decrease in blood pressure were more prominent in hypertensive patients than in normotensive volunteers. Administration of Nicardipine I.V. to normotensive volunteers at dosages of 0.25 to 3.0 mg/hr for eight hours produced changes of <5 mmHg in systolic blood pressure and <3 mmHg in diastolic blood pressure. An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced. In placebo-controlled trials, the mean increases in heart rate were 7 ± 1 bpm in postoperative patients and 8 ± 1 bpm in patients with severe hypertension at the end of the maintenance period. Hemodynamic studies following intravenous dosing in patients with coronary artery disease and normal or moderately abnormal left ventricular function have shown significant increases in ejection fraction and cardiac output with no significant change, or a small decrease, in left ventricular end-diastolic pressure (LVEDP). There is evidence that Nicardipine increases blood flow. Coronary dilatation induced by Nicardipine I.V. improves perfusion and aerobic metabolism in areas with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption. In patients with coronary artery disease, Nicardipine I.V., administered after beta-blockade, significantly improved systolic and diastolic left ventricular function. In congestive heart failure patients with impaired left ventricular function, Nicardipine I.V. increased cardiac output both at rest and during exercise. Decreases in left ventricular end-diastolic pressure were also observed. However, in some patients with severe left ventricular dysfunction, it may have a negative inotropic effect and could lead to worsened failure. “Coronary steal” has not been observed during treatment with Nicardipine I.V. (Coronary steal is the detrimental redistribution of coronary blood flow in patients with coronary artery disease from underperfused areas toward better perfused areas.) Nicardipine I.V. has been shown to improve systolic shortening in both normal and hypokinetic segments of myocardial muscle. Radionuclide angiography has confirmed that wall motion remained improved during increased oxygen demand. (Occasional patients have developed increased angina upon receiving oral nicardipine. Whether this represents coronary steal in these patients, or is the result of increased heart rate and decreased diastolic pressure, is not clear.) In patients with coronary artery disease, Nicardipine I.V. improves left ventricular diastolic distensibility during the early filling phase, probably due to a faster rate of myocardial relaxation in previously underperfused areas. There is little or no effect on normal myocardium, suggesting the improvement is mainly by indirect mechanisms such as afterload reduction and reduced ischemia. Nicardipine I.V. has no negative effect on myocardial relaxation at therapeutic doses. The clinical benefits of these properties have not yet been demonstrated. ### Electrophysiologic Effects In general, no detrimental effects on the cardiac conduction system have been seen with Nicardipine I.V. During acute electrophysiologic studies, it increased heart rate and prolonged the corrected QT interval to a minor degree. It did not affect sinus node recovery or SA conduction times. The PA, AH, and HV intervals* or the functional and effective refractory periods of the atrium were not prolonged. The relative and effective refractory periods of the His-Purkinje system were slightly shortened. - PA = conduction time from high to low right atrium; AH = conduction time from low right atrium to His bundle deflection, or AV nodal conduction time; HV = conduction time through the His bundle and the bundle branch-Purkinje system. ## Hepatic Function Because the liver extensively metabolizes nicardipine, plasma concentrations are influenced by changes in hepatic function. In a clinical study with oral nicardipine in patients with severe liver disease, plasma concentrations were elevated and the half-life was prolonged. Similar results were obtained in patients with hepatic disease when Nicardipine I.V. (nicardipine hydrochloride) was administered for 24 hours at 0.6 mg/hr. ## Renal Function When Nicardipine I.V. was given to mild to moderate hypertensive patients with moderate degrees of renal impairment, significant reduction in glomerular filtration rate (GFR) and effective renal plasma flow (RPF) was observed. No significant differences in liver blood flow were observed in these patients. A significantly lower systemic clearance and higher area under the curve (AUC) were observed. When oral nicardipine (20 mg or 30 mg TID) was given to hypertensive patients with impaired renal function, mean plasma concentrations, AUC, and Cmaxwere approximately two-fold higher than in healthy controls. There is a transient increase in electrolyte excretion, including sodium. Acute bolus administration of Nicardipine I.V. (2.5 mg) in healthy volunteers decreased mean arterial pressure and renal vascular resistance; glomerular filtration rate (GFR), renal plasma flow (RPF), and the filtration fraction were unchanged. In healthy patients undergoing abdominal surgery, Nicardipine I.V. (10 mg over 20 minutes) increased GFR with no change in RPF when compared with placebo. In hypertensive type II diabetic patients with nephropathy, oral nicardipine (20 mg TID) did not change RPF and GFR, but reduced renal vascular resistance. ## Pulmonary Function In two well-controlled studies of patients with obstructive airway disease treated with oral nicardipine, no evidence of increased bronchospasm was seen. In one of the studies, oral nicardipine improved forced expiratory volume 1 second (FEV1) and forced vital capacity (FVC) in comparison with metoprolol. Adverse experiences reported in a limited number of patients with asthma, reactive airway disease, or obstructive airway disease are similar to all patients treated with oral nicardipine. ## Pharmacokinetics ### Distribution Rapid dose-related increases in nicardipine plasma concentrations are seen during the first two hours after the start of an infusion of Nicardipine I.V. Plasma concentrations increase at a much slower rate after the first few hours, and approach steady state at 24 to 48 hours. The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (>65 years) and young healthy adults. On termination of the infusion, nicardipine concentrations decrease rapidly, with at least a 50% decrease during the first two hours post-infusion. The effects of nicardipine on blood pressure significantly correlate with plasma concentrations. Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range. Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase (α-half-life of 2.7 minutes), an intermediate phase (β-half-life of 44.8 minutes), and a slow terminal phase (γ-half-life of 14.4 hours) that can only be detected after long-term infusions. Total plasma clearance (Cl) is 0.4 L/hr•kg, and the apparent volume of distribution (Vd) using a non-compartment model is 8.3 L/kg. The pharmacokinetics of Nicardipine I.V. are linear over the dosage range of 0.5 to 40.0 mg/hr. ## Metabolism and Excretion Nicardipine I.V. has been shown to be rapidly and extensively metabolized by the liver. Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes. After coadministration of a radioactive intravenous dose of Nicardipine I.V. with an oral 30 mg dose given every 8 hours, 49% of the radioactivity was recovered in the urine and 43% in the feces within 96 hours. None of the dose was recovered as unchanged nicardipine. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility Rats treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of 5, 15, or 45 mg/kg/day) for two years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and three-month studies in the rat have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine (T4) levels with a consequent increase in plasma levels of thyroid stimulating hormone (TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid. In rats on an iodine deficient diet, nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementation. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100 mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes. There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for one year and no evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man. There was no evidence of a mutagenic potential of nicardipine in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronucleus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters. No impairment of fertility was seen in male or female rats administered nicardipine at oral doses as high as 100 mg/kg/day (human equivalent dose about 16 mg/kg/day, 8 times the maximum recommended oral dose). ## Reproductive and Developmental Toxicology Embryotoxicity, but no teratogenicity, was seen at intravenous doses of 10 mg nicardipine/kg/day in rats and 1 mg/kg/day in rabbits. These doses in the rat and rabbit are equivalent to human IV doses of about 1.6 mg/kg/day and 0.32 mg/kg/day respectively. (The total daily human dose delivered by a continuous IV infusion ranges from 1.2 to 6 mg/kg/day, depending on duration at different infusion rates ranging from 3 to 15 mg/hr as individual patients are titrated for optimal results.) Nicardipine was also embryotoxic when administered orally to pregnant Japanese White rabbits, during organogenesis, at 150 mg/kg/day (a dose associated with marked body weight gain suppression in the treated doe), but not at 50 mg/kg/day (human equivalent dose about 16 mg/kg/day or about 8 times the maximum recommended human oral dose). No adverse effects on the fetus were observed when New Zealand albino rabbits were treated orally, during organogenesis, with up to 100 mg nicardipine/kg/day (a dose associated with significant mortality in the treated doe). In pregnant rats administered nicardipine orally at doses of up to 100 mg/kg/day (human equivalent dose about 16 mg/kg/day) there was no evidence of embryotoxicity or teratogenicity. However, dystocia, reduced birth weight, reduced neonatal survival and reduced neonatal weight gain were noted. # Clinical Studies ## Effects In Hypertension In patients with mild to moderate chronic stable essential hypertension, Nicardipine I.V. (0.5 to 4.0 mg/hr) produced dose-dependent decreases in blood pressure. At the end of a 48-hour infusion at 4.0 mg/hr, the decreases were 26.0 mmHg (17%) in systolic blood pressure and 20.7 mmHg (20%) in diastolic blood pressure. In other settings (e.g., patients with severe or postoperative hypertension), Nicardipine I.V. (5 to 15 mg/hr) produced dose-dependent decreases in blood pressure. Higher infusion rates produced therapeutic responses more rapidly. The mean time to therapeutic response for severe hypertension, defined as diastolic blood pressure ≤95 mmHg or ≥25 mmHg decrease and systolic blood pressure ≤160 mmHg, was 77 ± 5.2 minutes. The average maintenance dose was 8.0 mg/hr. The mean time to therapeutic response for postoperative hypertension, defined as ≥15% reduction in diastolic or systolic blood pressure, was 11.5 ± 0.8 minutes. The average maintenance dose was 3.0 mg/hr.Deep vein thrombosis # How Supplied ## For Nicardipine capsule Nicardipine hydrochloride capsules are available containing 20 mg or 30 mg of nicardipine hydrochloride, USP. The 20 mg capsule is a hard-shell gelatin capsule with a medium blue-green opaque cap and an ivory opaque body axially imprinted with MYLAN over 1020 in black ink on both the cap and the body. They are available as follows: NDC 0378-1020-77 bottles of 90 capsules NDC 0378-1020-05 bottles of 500 capsules The 30 mg capsule is a hard-shell gelatin capsule with a bluish green opaque cap and a rich yellow opaque body axially imprinted with MYLAN over 1430 in black ink on both the cap and the body. They are available as follows: NDC 0378-1430-77 bottles of 90 capsules NDC 0378-1430-05 bottles of 500 capsules ## For Nicardipine Injection Nicardipine I.V. Injection is supplied as a single-use, ready-to-use, iso-osmotic solution for intravenous administration in a 200 mL GALAXY container with 40 mg (0.2 mg/mL) nicardipine hydrochloride in either dextrose or sodium chloride. ## Storage ## For Nicardipine capsule 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 using a child-resistant closure. ## For Nicardipine Injection Store at controlled room temperature 20° to 25°C (68° to 77°F), refer to USP Controlled Room Temperature. Protect from freezing. Avoid excessive heat. Protect from light, store in carton until ready to use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Nicardipine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Nicardipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cardene - Cardene IV - Cardene SR # Look-Alike Drug Names Nicardipine - Nifedipine Nicardipine - Nimodipine[10] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/CARDENE_I.V._adverse_reactions
80d3396a38d07d4789991054dab556f81524013b	wikidoc	CARD domain	CARD domain # Overview Caspase recruitment domains, or CARD domains, are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARD domains are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors. # Basic features CARD domains are a subclass of protein motif known as the death fold, which features an arrangement of six to seven antiparallel alpha helices with a hydrophobic core and an outer face composed of charged residues. Other motifs in this class include the pyrin domain (PYD), death domain (DD), and death effector domain (DED), all of which also function primarily in regulation of apoptosis and inflammatory responses. # CARD domains in apoptosis CARD domains were originally characterized based on their involvement in the regulation of caspase activation and apoptosis. The basic six-helix structure of the domain appears to be conserved as far back as the ced-3 and ced-4 genes in C. elegans, the organism in which several components of the apoptotic machinery were first characterized. CARD motifs are present on a number of proteins that promote apoptosis, primarily caspases 1,4,5,9, and 15 in mammals. # CARD domains in the mammalian immune response ### IL-1 and IL-18 processing A number of CARD proteins have been shown to play a role in regulating inflammation in response to bacterial and viral pathogens as well as to a variety of endogenous stress signals. Recently, studies on the NLR protein Ipaf-1 have provided insight into how CARD proteins participate in the immune response. Ipaf-1 features an N-terminal CARD domain, a nucleotide-binding domain, and C-terminal leucine-rich repeats (LRRs), thought to function in a similar fashion to those found in Toll-like receptors. The primary role of this molecule appears to be regulation of the proteolytic processing of pro-IL-1β and pro-IL-18 into their mature forms via association in a large complex known as the inflammasome. Upon activation of Ipaf-1 by the intracellular bacterium S. typhimurium or other stress signals, Ipaf-1 recruits a CARD-containing adapter termed ASC and caspase-1 in unknown stoichiometry via CARD-CARD association. This complex in turn leads to autoproteolytic activation of caspase-1 and subsequent IL-1β and IL-18 maturation. ### Antiviral signaling Recently, a subset of CARD proteins has been shown to participate in recognition of intracellular double-stranded RNA, a common constituent of a number of viral genomes, including the para- and orthomyxoviridae and rhabdoviridae. Unlike NLRs, these proteins, termed RIG-I and MDA5, contain twin N-terminal CARD domains and C-terminal RNA helicase domains that directly interact with and process the double-stranded viral RNA. This processing makes the CARD domains available for interaction with the CARD motif of IPS-1/MAVS/VISA/Cardif, a downstream adapter anchored in the mitochondria. Although the interactions between IPS-1 and RIG-I/MDA-5 have been shown in vitro, the nature of the complex formed upon viral detection has not been characterized. # Autoimmunity Because of their role as regulators of inflammation, constitutive activation of certain CARD proteins, either conferred by mutation or by constant presence of stress signals, has been suggested to play a causative role in a number of inflammatory syndromes. Gain-of-function mutations in the intracellular NOD2 protein has been linked to increased risk for Crohn's disease. Activating mutations in at least two related PYD-containing proteins, cryopyrin/CIAS-1 and pyrin/MEFV, have been linked to Muckle-Wells Syndrome and familial Mediterranean fever, respectively. # List of CARD containing proteins - BIRC2 baculoviral Inhibitor of apoptosis (IAP) repeat-containing 2, also known as C-IAP1 - BIRC3 baculoviral IAP repeat-containing 3, also known as C-IAP2 - Caspase 1: caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase; ICE) - Caspase 2: caspase 2, apoptosis-related cysteine peptidase - Caspase 4: caspase 4, apoptosis-related cysteine peptidase - Caspase 5: caspase 5, apoptosis-related cysteine peptidase - Caspase 9: caspase 9, apoptosis-related cysteine peptidase - Caspase 12: caspase 12, apoptosis-related cysteine peptidase - Caspase 13: caspase 13, apoptosis-related cysteine peptidase - ICEBERG: caspase 1 inhibitor iceberg - Pseudo-ICE:Caspase-1 dominant-negative inhibitor Pseudo-ICE, also known as COP1 - MDA-5: Melanoma differentiation-associated protein 5, also called Interferon-induced helicase C domain-containing protein 1 (IFIH1) - MAVS: Mitochondrial antiviral-signaling protein also known as CARD adapter inducing interferon-beta (Cardif) - CRADD: Caspase and RIP adapter with death domain also known as RIP-associated protein with a death domain (RAIDD) - RAIDD-2: Death adaptor molecule RAIDD-2 - RIG-I: Retinoic acid-inducible gene 1 protein, also known as DEAD-box protein 58 (DDX58) - RIPK2: receptor-interacting serine-threonine kinase 2 (also called cardiak, RIP2 or RICK kinase) - Bcl10: B-cell lymphoma/leukemia 10 protein - BINCA: Bcl10-interacting CARD protein or BinCARD, also called chromosome 9 open reading frame 89 (C9orf89) - CARD6: caspase recruitment domain family, member 6 - CARD8/CARDINAL: caspase recruitment domain family, member 8 - CARD9: caspase recruitment domain family, member 9 - CARD10: caspase recruitment domain family, member 10 (also called CARMA3) - CARD11: caspase recruitment domain family, member 11 (also called CARMA1) - CARD14: caspase recruitment domain family, member 14 (also called CARMA2) - APAF1: apoptotic peptidase activating factor 1 (also called CED4) - GLAVA1: glavaris peptidase activating factor 1 (also called GLAV1) - IPAF: Ice protease-activating factor, also known as NLR family, card domain containing 4 (NLRC4), CARD, LRR, and NACHT-containing protein (CLAN) and Caspase recruitment domain-containing protein 12 (CARD12) - NOD1: nucleotide-binding oligomerization domain containing 1 - NOD2: nucleotide-binding oligomerization domain containing 2 - NLRP1: NLR family, pyrin domain containing 1 (previously called NALP1) - NOL3: nucleolar protein 3 (apoptosis repressor with CARD domain) - PYCARD: PYD and CARD domain containing protein (also called ASC) - IPS1: RIG-I and MDA adaptor protein	CARD domain # Overview Caspase recruitment domains, or CARD domains, are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARD domains are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors. # Basic features CARD domains are a subclass of protein motif known as the death fold, which features an arrangement of six to seven antiparallel alpha helices with a hydrophobic core and an outer face composed of charged residues. Other motifs in this class include the pyrin domain (PYD), death domain (DD), and death effector domain (DED), all of which also function primarily in regulation of apoptosis and inflammatory responses. # CARD domains in apoptosis CARD domains were originally characterized based on their involvement in the regulation of caspase activation and apoptosis. The basic six-helix structure of the domain appears to be conserved as far back as the ced-3 and ced-4 genes in C. elegans, the organism in which several components of the apoptotic machinery were first characterized. CARD motifs are present on a number of proteins that promote apoptosis, primarily caspases 1,4,5,9, and 15 in mammals. # CARD domains in the mammalian immune response ### IL-1 and IL-18 processing A number of CARD proteins have been shown to play a role in regulating inflammation in response to bacterial and viral pathogens as well as to a variety of endogenous stress signals. Recently, studies on the NLR protein Ipaf-1 have provided insight into how CARD proteins participate in the immune response. Ipaf-1 features an N-terminal CARD domain, a nucleotide-binding domain, and C-terminal leucine-rich repeats (LRRs), thought to function in a similar fashion to those found in Toll-like receptors. The primary role of this molecule appears to be regulation of the proteolytic processing of pro-IL-1β and pro-IL-18 into their mature forms via association in a large complex known as the inflammasome. Upon activation of Ipaf-1 by the intracellular bacterium S. typhimurium or other stress signals, Ipaf-1 recruits a CARD-containing adapter termed ASC and caspase-1 in unknown stoichiometry via CARD-CARD association. This complex in turn leads to autoproteolytic activation of caspase-1 and subsequent IL-1β and IL-18 maturation. ### Antiviral signaling Recently, a subset of CARD proteins has been shown to participate in recognition of intracellular double-stranded RNA, a common constituent of a number of viral genomes, including the para- and orthomyxoviridae and rhabdoviridae. Unlike NLRs, these proteins, termed RIG-I and MDA5, contain twin N-terminal CARD domains and C-terminal RNA helicase domains that directly interact with and process the double-stranded viral RNA. This processing makes the CARD domains available for interaction with the CARD motif of IPS-1/MAVS/VISA/Cardif, a downstream adapter anchored in the mitochondria. Although the interactions between IPS-1 and RIG-I/MDA-5 have been shown in vitro, the nature of the complex formed upon viral detection has not been characterized. # Autoimmunity Because of their role as regulators of inflammation, constitutive activation of certain CARD proteins, either conferred by mutation or by constant presence of stress signals, has been suggested to play a causative role in a number of inflammatory syndromes. Gain-of-function mutations in the intracellular NOD2 protein has been linked to increased risk for Crohn's disease. Activating mutations in at least two related PYD-containing proteins, cryopyrin/CIAS-1 and pyrin/MEFV, have been linked to Muckle-Wells Syndrome and familial Mediterranean fever, respectively. # List of CARD containing proteins - BIRC2 baculoviral Inhibitor of apoptosis (IAP) repeat-containing 2, also known as C-IAP1 [1] - BIRC3 baculoviral IAP repeat-containing 3, also known as C-IAP2 [2] - Caspase 1: caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase; ICE) [3] - Caspase 2: caspase 2, apoptosis-related cysteine peptidase [4] - Caspase 4: caspase 4, apoptosis-related cysteine peptidase [5] - Caspase 5: caspase 5, apoptosis-related cysteine peptidase [6] - Caspase 9: caspase 9, apoptosis-related cysteine peptidase [7] - Caspase 12: caspase 12, apoptosis-related cysteine peptidase [8] - Caspase 13: caspase 13, apoptosis-related cysteine peptidase [9] - ICEBERG: caspase 1 inhibitor iceberg [10] - Pseudo-ICE:Caspase-1 dominant-negative inhibitor Pseudo-ICE, also known as COP1 [11] - MDA-5: Melanoma differentiation-associated protein 5, also called Interferon-induced helicase C domain-containing protein 1 (IFIH1) [12] - MAVS: Mitochondrial antiviral-signaling protein also known as CARD adapter inducing interferon-beta (Cardif) [13] - CRADD: Caspase and RIP adapter with death domain also known as RIP-associated protein with a death domain (RAIDD) [14] - RAIDD-2: Death adaptor molecule RAIDD-2 [15] - RIG-I: Retinoic acid-inducible gene 1 protein, also known as DEAD-box protein 58 (DDX58) [16] - RIPK2: receptor-interacting serine-threonine kinase 2 (also called cardiak, RIP2 or RICK kinase) [17] - Bcl10: B-cell lymphoma/leukemia 10 protein [18] - BINCA: Bcl10-interacting CARD protein or BinCARD, also called chromosome 9 open reading frame 89 (C9orf89) [19] - CARD6: caspase recruitment domain family, member 6 [20] - CARD8/CARDINAL: caspase recruitment domain family, member 8 [21] - CARD9: caspase recruitment domain family, member 9 [22] - CARD10: caspase recruitment domain family, member 10 (also called CARMA3) [23] - CARD11: caspase recruitment domain family, member 11 (also called CARMA1) [24] - CARD14: caspase recruitment domain family, member 14 (also called CARMA2) [25] - APAF1: apoptotic peptidase activating factor 1 (also called CED4) [26] - GLAVA1: glavaris peptidase activating factor 1 (also called GLAV1) [27] - IPAF: Ice protease-activating factor, also known as NLR family, card domain containing 4 (NLRC4), CARD, LRR, and NACHT-containing protein (CLAN) and Caspase recruitment domain-containing protein 12 (CARD12) [28] - NOD1: nucleotide-binding oligomerization domain containing 1 [29] - NOD2: nucleotide-binding oligomerization domain containing 2 [30] - NLRP1: NLR family, pyrin domain containing 1 (previously called NALP1) [31] - NOL3: nucleolar protein 3 (apoptosis repressor with CARD domain) [32] - PYCARD: PYD and CARD domain containing protein (also called ASC) [33] - IPS1: RIG-I and MDA adaptor protein Template:Incomplete list	https://www.wikidoc.org/index.php/CARD_domain
5a003b4cd9ba5f5a1eaaec043ffe047888a156bb	wikidoc	CBLB (gene)	CBLB (gene) CBL-B is an E3 ubiquitin-protein ligase that in humans is encoded by the CBLB gene. CBLB is a member of the CBL gene family. # Function CBL-B functions as a negative regulator of T-cell activation. CBL-B expression in T cells causes ligand-induced T cell receptor down-modulation, controlling the activation degree of T cells during antigen presentation. # Clinical significance Mutation of the CBLB gene has been associated with autoimmune conditions such as type 1 diabetes. # Interactions CBLB has been shown to interact with: - CRKL, - Epidermal growth factor receptor, - Grb2, - NEDD4, - PIK3R1, and - SH3KBP1.	CBLB (gene) CBL-B is an E3 ubiquitin-protein ligase that in humans is encoded by the CBLB gene.[1][2] CBLB is a member of the CBL gene family. # Function CBL-B functions as a negative regulator of T-cell activation.[3] CBL-B expression in T cells causes ligand-induced T cell receptor down-modulation, controlling the activation degree of T cells during antigen presentation.[4][5] # Clinical significance Mutation of the CBLB gene has been associated with autoimmune conditions such as type 1 diabetes.[6][7] # Interactions CBLB has been shown to interact with: - CRKL,[8] - Epidermal growth factor receptor,[9][10] - Grb2,[8][11] - NEDD4,[12] - PIK3R1,[8][11] and - SH3KBP1.[13]	https://www.wikidoc.org/index.php/CBLB_(gene)
9013fa004cd9335ab8b28cd7e1f16a35138acee2	wikidoc	CBX5 (gene)	CBX5 (gene) Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene. It is a highly conserved, non-histone protein part of the heterochromatin family. The protein itself is more commonly called (in humans) HP1α. Heterochromatin protein-1 (HP1) has an N-terminal domain that acts on methylated lysines residues leading to epigenetic repression. The C-terminal of this protein has a chromo shadow-domain (CSD) that is responsible for homodimerizing, as well as interacting with a variety of chromatin-associated, non-histone proteins. # Structure HP1α is 191 amino acids in length containing 6 exons. As mentioned above, this protein contains two domains, an N-terminal chromodomain (CD) and a C- terminal chromoshadow domain (CSD). The CD binds with histone 3 through a methylated lysine residue at position 9 (H3K9) while the C-terminal CSD homodimerizes and interacts with a variety of other chromatin-associated, non-histone related proteins. Connecting these two domains is the hinge region. ## Chromodomain Once translated, the chromodomain will take on a globular conformation consisting of three β-sheets and one α-helix. The β-sheets are packed up against the helix at the carboxy terminal segment. The charges on the β sheets are negative thus making it difficult for it to bind to the DNA as a DNA-binding motif. Instead, HP1α binds to the histones as a protein interaction motif. Specific binding to CD to the methylated H3K9 is mediated by three hydrophobic side chains called the "hydrophobic box". Other sites on HP1 will interact with the H3 tails from neighbouring histones which will give structure to the flexible N-terminal tail of the histones. Neighbouring H3 histones can affect HP1 binding by post-translationally modifying the tails. ## Chromoshadow domain The CSD much resembles that of the CD. It too has a globular conformation containing three β-sheets, however it possesses two α-helices as opposed to just the one in the CD. The CSD readily homodimerizes in vitro and as a result forms a groove which can accommodate HP1 associated proteins that have a specific consensus sequence: PxVxL, where P is Proline, V is Valine, L is Leucine and x is any amino acid. # Mechanism of action HP1α primarily functions as a gene silencer, which is dependent on the interactions between the CD and the methyl H3K9 mark. The hydrophobic box on the CD provides the appropriate environment for the methylated lysine residue. While the exact mechanism of how gene silencing is done is unknown, experimental data concluded the rapid exchange of biological macromolecules in and out of the heterochromatin region. This suggests HP1 isn't acting as a glue holding the heterochromatin together, but rather there are competing molecules within that interact in various ways to create a closed complex leading to gene repression or an open, euchromatin structure with gene activation. HP1 concentration is higher and more static in areas of the chromosome where methylated H3K9 residues reside, giving the chromosome its closed, gene-repressed heterochromatin structure. It has also been shown that the more methylated the H3 lysine is, the higher the affinity HP1 has for it. That is, trimethylated lysine residues bind tighter to HP1 than dimethylated residues, which bind better than monomethylated residues. The localisation driving factor is currently unknown. # Evolutionary conservation HP1α is a highly evolutionary conserved protein, existing in species such a Schizosaccharomyces pombe, a type of yeast, all the way to humans. The N-terminal chromodomain and C-terminal chromoshadow domain appear to be much more conserved (approximately 50-70% amino acid similarity) than the hinge region (approximately 25-30% similarity with the Drosophila HP1 homolog). # Interactions CBX5 (gene) has been shown to interact with: - CBX1, - CBX3, - CHAF1A, - DNMT3B, - HDAC4, - HDAC9, - Histone deacetylase 5, - Ku70, - Lamin B receptor, - MBD1, - MIS12, - SMARCA4, - SUV39H1, - TAF4, and - TRIM28. - STAT5A,	CBX5 (gene) Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene.[1][2] It is a highly conserved, non-histone protein part of the heterochromatin family. The protein itself is more commonly called (in humans) HP1α.[citation needed] Heterochromatin protein-1 (HP1) has an N-terminal domain that acts on methylated lysines residues leading to epigenetic repression.[3] The C-terminal of this protein has a chromo shadow-domain (CSD) that is responsible for homodimerizing, as well as interacting with a variety of chromatin-associated, non-histone proteins.[4] # Structure HP1α is 191 amino acids in length containing 6 exons.[3][4] As mentioned above, this protein contains two domains, an N-terminal chromodomain (CD) and a C- terminal chromoshadow domain (CSD). The CD binds with histone 3 through a methylated lysine residue at position 9 (H3K9) while the C-terminal CSD homodimerizes and interacts with a variety of other chromatin-associated, non-histone related proteins.[4] Connecting these two domains is the hinge region.[5] ## Chromodomain Once translated, the chromodomain will take on a globular conformation consisting of three β-sheets and one α-helix. The β-sheets are packed up against the helix at the carboxy terminal segment.[5] The charges on the β sheets are negative thus making it difficult for it to bind to the DNA as a DNA-binding motif. Instead, HP1α binds to the histones as a protein interaction motif.[4] Specific binding to CD to the methylated H3K9 is mediated by three hydrophobic side chains called the "hydrophobic box". Other sites on HP1 will interact with the H3 tails from neighbouring histones which will give structure to the flexible N-terminal tail of the histones. Neighbouring H3 histones can affect HP1 binding by post-translationally modifying the tails.[5] ## Chromoshadow domain The CSD much resembles that of the CD. It too has a globular conformation containing three β-sheets, however it possesses two α-helices as opposed to just the one in the CD.[5] The CSD readily homodimerizes in vitro and as a result forms a groove which can accommodate HP1 associated proteins that have a specific consensus sequence: PxVxL, where P is Proline, V is Valine, L is Leucine and x is any amino acid.[4] # Mechanism of action HP1α primarily functions as a gene silencer, which is dependent on the interactions between the CD and the methyl H3K9 mark.[6] The hydrophobic box on the CD provides the appropriate environment for the methylated lysine residue. While the exact mechanism of how gene silencing is done is unknown, experimental data concluded the rapid exchange of biological macromolecules in and out of the heterochromatin region. This suggests HP1 isn't acting as a glue holding the heterochromatin together, but rather there are competing molecules within that interact in various ways to create a closed complex leading to gene repression or an open, euchromatin structure with gene activation. HP1 concentration is higher and more static in areas of the chromosome where methylated H3K9 residues reside, giving the chromosome its closed, gene-repressed heterochromatin structure.[5] It has also been shown that the more methylated the H3 lysine is, the higher the affinity HP1 has for it. That is, trimethylated lysine residues bind tighter to HP1 than dimethylated residues, which bind better than monomethylated residues. The localisation driving factor is currently unknown.[5] # Evolutionary conservation HP1α is a highly evolutionary conserved protein, existing in species such a Schizosaccharomyces pombe, a type of yeast, all the way to humans.[5] The N-terminal chromodomain and C-terminal chromoshadow domain appear to be much more conserved (approximately 50-70% amino acid similarity) than the hinge region (approximately 25-30% similarity with the Drosophila HP1 homolog).[5] # Interactions CBX5 (gene) has been shown to interact with: - CBX1,[7] - CBX3,[7] - CHAF1A,[8][9] - DNMT3B,[10] - HDAC4,[11] - HDAC9,[11] - Histone deacetylase 5,[11] - Ku70,[12] - Lamin B receptor,[13] - MBD1,[8][14] - MIS12,[15] - SMARCA4,[16] - SUV39H1,[11][14][17] - TAF4,[18] and - TRIM28.[7][9][16][19] - STAT5A,[20]	https://www.wikidoc.org/index.php/CBX5_(gene)
dc29e5621d4b892da9c758d85bfb72e79e3aa5f0	wikidoc	CCNC (gene)	CCNC (gene) Cyclin-C is a protein that in humans is encoded by the CCNC gene. The protein encoded by this gene is a member of the cyclin family of proteins. The encoded protein interacts with cyclin-dependent kinase 8 and induces the phosphorylation of the carboxy-terminal domain of the large subunit of RNA polymerase II. The level of mRNAs for this gene peaks in the G1 phase of the cell cycle. Two transcript variants encoding different isoforms have been found for this gene. # Interactions CCNC (gene) has been shown to interact with Estrogen receptor alpha and Cyclin-dependent kinase 8.	CCNC (gene) Cyclin-C is a protein that in humans is encoded by the CCNC gene.[1][2] The protein encoded by this gene is a member of the cyclin family of proteins. The encoded protein interacts with cyclin-dependent kinase 8 and induces the phosphorylation of the carboxy-terminal domain of the large subunit of RNA polymerase II. The level of mRNAs for this gene peaks in the G1 phase of the cell cycle. Two transcript variants encoding different isoforms have been found for this gene.[2] # Interactions CCNC (gene) has been shown to interact with Estrogen receptor alpha[3] and Cyclin-dependent kinase 8.[3][4][5][6][7]	https://www.wikidoc.org/index.php/CCNC_(gene)
e13f97ff6801cfbe809553a0f83ac83c0330984b	wikidoc	CCR3 (gene)	CCR3 (gene) C-C chemokine receptor type 3 is a protein that in humans is encoded by the CCR3 gene. CCR3 has also recently been designated CD193 (cluster of differentiation 193). # Function The protein encoded by this gene is a receptor for C-C type chemokines. It belongs to family 1 of the G protein-coupled receptors. This receptor binds and responds to a variety of chemokines, including eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). It is highly expressed in eosinophils and basophils, and is also detected in TH1 and TH2 cells, as well as in airway epithelial cells. This receptor may contribute to the accumulation and activation of eosinophils and other inflammatory cells in the allergic airway, and possibly at sites of parasitic infection. It is also known to be an entry co-receptor for HIV-1. This gene and seven other chemokine receptor genes form a chemokine receptor gene cluster on the chromosomal region 3p21. Alternatively spliced transcript variants encoding the same protein have been described.	CCR3 (gene) C-C chemokine receptor type 3 is a protein that in humans is encoded by the CCR3 gene.[1] CCR3 has also recently been designated CD193 (cluster of differentiation 193). # Function The protein encoded by this gene is a receptor for C-C type chemokines. It belongs to family 1 of the G protein-coupled receptors. This receptor binds and responds to a variety of chemokines, including eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). It is highly expressed in eosinophils and basophils,[2] and is also detected in TH1 and TH2 cells, as well as in airway epithelial cells. This receptor may contribute to the accumulation and activation of eosinophils and other inflammatory cells in the allergic airway, and possibly at sites of parasitic infection. It is also known to be an entry co-receptor for HIV-1. This gene and seven other chemokine receptor genes form a chemokine receptor gene cluster on the chromosomal region 3p21. Alternatively spliced transcript variants encoding the same protein have been described.[1]	https://www.wikidoc.org/index.php/CCR3_(gene)
ec417fc2eb91fc7e6041bb4d21c5155058a2f01e	wikidoc	CCR8 (gene)	CCR8 (gene) Chemokine (C-C motif) receptor 8, also known as CCR8, is a protein which in humans is encoded by the CCR8 gene. CCR8 has also recently been designated CDw198 (cluster of differentiation w198). # Function This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptors are important for the migration of various cell types into the inflammatory sites. This receptor protein preferentially expresses in the thymus. The ligand of the CCR8 is CCL1. CCL8 also functions as a CCR8 agonist. Studies of this receptor and its ligands suggested its role in regulation of monocyte chemotaxis and thymic cell apoptosis. More specifically, this receptor may contribute to the proper positioning of activated T cells within the antigenic challenge sites and specialized areas of lymphoid tissues. This gene is located at the chemokine receptor gene cluster region.	CCR8 (gene) Chemokine (C-C motif) receptor 8, also known as CCR8, is a protein which in humans is encoded by the CCR8 gene.[1] CCR8 has also recently been designated CDw198 (cluster of differentiation w198). # Function This gene encodes a member of the beta chemokine receptor family, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptors are important for the migration of various cell types into the inflammatory sites. This receptor protein preferentially expresses in the thymus. The ligand of the CCR8 is CCL1.[2] CCL8 also functions as a CCR8 agonist.[3] Studies of this receptor and its ligands suggested its role in regulation of monocyte chemotaxis and thymic cell apoptosis. More specifically, this receptor may contribute to the proper positioning of activated T cells within the antigenic challenge sites and specialized areas of lymphoid tissues. This gene is located at the chemokine receptor gene cluster region.[1]	https://www.wikidoc.org/index.php/CCR8_(gene)
c4cdb782c6aebc5834f317eaf99dce427a037a87	wikidoc	CD82 (gene)	CD82 (gene) CD82 (Cluster of Differentiation 82) is a human protein encoded by the CD82 gene. This metastasis suppressor gene product is a membrane glycoprotein that is a member of the transmembrane 4 superfamily. Expression of this gene has been shown to be downregulated in tumor progression of human cancers and can be activated by p53 through a consensus binding sequence in the promoter. Its expression and that of p53 are strongly correlated, and the loss of expression of these two proteins is associated with poor survival for prostate cancer patients. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. # Interactions CD82 (gene) has been shown to interact with CD19, CD63 and CD234	CD82 (gene) CD82 (Cluster of Differentiation 82) is a human protein encoded by the CD82 gene.[1] This metastasis suppressor gene product is a membrane glycoprotein that is a member of the transmembrane 4 superfamily. Expression of this gene has been shown to be downregulated in tumor progression of human cancers and can be activated by p53 through a consensus binding sequence in the promoter. Its expression and that of p53 are strongly correlated, and the loss of expression of these two proteins is associated with poor survival for prostate cancer patients. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[1] # Interactions CD82 (gene) has been shown to interact with CD19,[2][3] CD63[4] and CD234[5]	https://www.wikidoc.org/index.php/CD82_(gene)
ff3074063974f9061feafb70e05283dd22f92183	wikidoc	CDH1 (gene)	CDH1 (gene) Cadherin-1 also known as CAM 120/80 or epithelial cadherin (E-cadherin) or uvomorulin is a protein that in humans is encoded by the CDH1 gene. CDH1 has also been designated as CD324 (cluster of differentiation 324). It is a tumor suppressor gene. # Function Cadherin-1 is a classical member of the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells, and the cytoplasmic domain is required for internalization. Identified transcript variants arise from mutation at consensus splice sites. E-cadherin (epithelial) is the most well-studied member of the cadherin family. It consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and an intracellular domain that binds p120-catenin and beta-catenin. The intracellular domain contains a highly-phosphorylated region vital to beta-catenin binding and, therefore, to E-cadherin function. Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of actin-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the cytoskeleton. E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction. In adult tissues, E-cadherin is expressed in epithelial tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface. Cell-cell interactions mediated by E-cadherin are crucial to blastula formation in many animals. # Clinical significance Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis. E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues. E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive ductal carcinoma, E-cadherin expression is markedly reduced or absent in the great majority of invasive lobular carcinomas when studied by immunohistochemistry. # Interactions CDH1 (gene) has been shown to interact with - CBLL1, - CDC27, - CDON, - CDH3, - C-Met, - CTNND1, - CTNNB1, - CTNNA1 - FOXM1, - HDAC1, - HDAC2, - IQGAP1, - FYN, - NEDD9, - Plakoglobin, - Vinculin, - PTPmu(PTPRM) - PTPrho(PTPRT) # Cadherin-1 and cancer ## Cadherin-1 in metastasis Transitions between epithelial and mesenchymal states play important roles in embryonic development and cancer metastasis. E-cadherin level changes in EMT (epithelial-mesenchymal transition) and MET (mesenchymal-epithelial transition). E-cadherin acts as an invasion suppressor and a classical tumor suppressor gene in pre-invasive lobular breast carcinoma. 1. E-cadherin in EMT: E-cadherin is a crucial type of cell-cell adhesion to hold the epithelial cells tight together. E-cadherin can sequester β-catenin on the cell membrane by the cytoplasmic tail of E-cadherin. Loss of E-cadherin expression results in releasing β-catenin into the cytoplasm. Liberated β-catenin molecules may migrate into the nucleus and trigger the expression of EMT-inducing transcription factors. Together with other mechanisms, such as constitutive RTK activation, E-cadherin loss can lead cancer cells to the mesenchymal state and undergo metastasis. E-cadherin is an important switch in EMT. 2. E-cadherin in MET: The mesenchymal state cancer cells migrate to new sites and may undergo METs in certain favorable microenvironment. For example, the cancer cells can recognize differentiated epithelial cell features in the new sites and upregulate E-cadherin expression. Those cancer cells can form cell-cell adhesions again and return to an epithelial state. ## Cancer examples - Inactivation of CDH1 (accompany with loss of the wild-type allele) in 56% of lobular breast carcinomas. - Inactivation of CDH1 in 50% of diffuse gastric carcinomas. - Complete loss of E-cadherin protein expression in 84% of lobular breast carcinomas. ## Genetic and epigenetic control of CDH1 Several proteins such as SNAI1/SNAIL, ZFHX1B/SIP1, SNAI2/SLUG, TWIST1 and DeltaEF1 have been found to downregulate E-cadherin expression. When expression of those transcription factors is altered, transcriptional repressors of E-cadherin were overexpressed in tumor cells. Another group of genes, such as AML1, p300 and HNF3, can upregulate the expression of E-cadherin. In order to study the epigenetic regulation of E-cadherin, M Lombaerts et al. performed a genome wide expression study on 27 human mammary cell lines. Their results revealed two main clusters that have the fibroblastic or epithelial phenotype, respectively. In close examination, the clusters showing fibroblast phenotypes only have either partial or complete CDH1 promoter methylation, while the clusters with epithelial phenotypes have both wild-type cell lines and cell lines with mutant CDH1 status. The authors also found that EMT can happen in breast cancer cell lines with hypermethylation of CDH1 promoter, but in breast cancer cell lines with a CDH1 mutational inactivation EMT cannot happen. It contradicts the hypothesis that E-cadherin loss is the initial or primary cause for EMT. In conclusion, the results suggest that “E-cadherin transcriptional inactivation is an epi-phenomenon and part of an entire program, with much more severe effects than loss of E-cadherin expression alone”. Other studies also show that epigenetic regulation of E-cadherin expression occurs during metastasis. The methylation patterns of the E-cadherin 5’ CpG island are not stable. During metastatic progression of many cases of epithelial tumors, a transient loss of E-cadherin is seen and the heterogeneous loss of E-cadherin expression results from a heterogeneous pattern of promoter region methylation of E-cadherin.	CDH1 (gene) Cadherin-1 also known as CAM 120/80 or epithelial cadherin (E-cadherin) or uvomorulin is a protein that in humans is encoded by the CDH1 gene.[1] CDH1 has also been designated as CD324 (cluster of differentiation 324). It is a tumor suppressor gene.[2][3] # Function Cadherin-1 is a classical member of the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells, and the cytoplasmic domain is required for internalization. Identified transcript variants arise from mutation at consensus splice sites.[4] E-cadherin (epithelial) is the most well-studied member of the cadherin family. It consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and an intracellular domain that binds p120-catenin and beta-catenin. The intracellular domain contains a highly-phosphorylated region vital to beta-catenin binding and, therefore, to E-cadherin function.[citation needed] Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of actin-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the cytoskeleton. E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction.[citation needed] In adult tissues, E-cadherin is expressed in epithelial tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface.[citation needed] Cell-cell interactions mediated by E-cadherin are crucial to blastula formation in many animals.[5] # Clinical significance Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis.[6][7] E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues.[7] E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive ductal carcinoma, E-cadherin expression is markedly reduced or absent in the great majority of invasive lobular carcinomas when studied by immunohistochemistry.[8] # Interactions CDH1 (gene) has been shown to interact with - CBLL1,[9] - CDC27,[10] - CDON,[11] - CDH3,[12] - C-Met,[13] - CTNND1,[14][15][16][17][18][19][20][21] - CTNNB1,[11][13][16][17][19][20][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] - CTNNA1[16][30][31][32][37] - FOXM1,[39] - HDAC1,[40] - HDAC2,[40] - IQGAP1,[41] - FYN,[19] - NEDD9,[42] - Plakoglobin,[16][17][43][44][45] - Vinculin,[17][24] - PTPmu(PTPRM)[46][47] - PTPrho(PTPRT)[48] # Cadherin-1 and cancer ## Cadherin-1 in metastasis Transitions between epithelial and mesenchymal states play important roles in embryonic development and cancer metastasis. E-cadherin level changes in EMT (epithelial-mesenchymal transition) and MET (mesenchymal-epithelial transition). E-cadherin acts as an invasion suppressor and a classical tumor suppressor gene in pre-invasive lobular breast carcinoma.[49] 1. E-cadherin in EMT: E-cadherin is a crucial type of cell-cell adhesion to hold the epithelial cells tight together. E-cadherin can sequester β-catenin on the cell membrane by the cytoplasmic tail of E-cadherin. Loss of E-cadherin expression results in releasing β-catenin into the cytoplasm. Liberated β-catenin molecules may migrate into the nucleus and trigger the expression of EMT-inducing transcription factors. Together with other mechanisms, such as constitutive RTK activation, E-cadherin loss can lead cancer cells to the mesenchymal state and undergo metastasis. E-cadherin is an important switch in EMT.[49] 2. E-cadherin in MET: The mesenchymal state cancer cells migrate to new sites and may undergo METs in certain favorable microenvironment. For example, the cancer cells can recognize differentiated epithelial cell features in the new sites and upregulate E-cadherin expression. Those cancer cells can form cell-cell adhesions again and return to an epithelial state.[49] ## Cancer examples - Inactivation of CDH1 (accompany with loss of the wild-type allele) in 56% of lobular breast carcinomas.[50][51] - Inactivation of CDH1 in 50% of diffuse gastric carcinomas.[52] - Complete loss of E-cadherin protein expression in 84% of lobular breast carcinomas.[53] ## Genetic and epigenetic control of CDH1 Several proteins such as SNAI1/SNAIL,[54][55] ZFHX1B/SIP1,[56] SNAI2/SLUG,[57][58] TWIST1[59] and DeltaEF1[60] have been found to downregulate E-cadherin expression. When expression of those transcription factors is altered, transcriptional repressors of E-cadherin were overexpressed in tumor cells.[54][55][56][57][59][60] Another group of genes, such as AML1, p300 and HNF3,[61] can upregulate the expression of E-cadherin.[62] In order to study the epigenetic regulation of E-cadherin, M Lombaerts et al. performed a genome wide expression study on 27 human mammary cell lines. Their results revealed two main clusters that have the fibroblastic or epithelial phenotype, respectively. In close examination, the clusters showing fibroblast phenotypes only have either partial or complete CDH1 promoter methylation, while the clusters with epithelial phenotypes have both wild-type cell lines and cell lines with mutant CDH1 status. The authors also found that EMT can happen in breast cancer cell lines with hypermethylation of CDH1 promoter, but in breast cancer cell lines with a CDH1 mutational inactivation EMT cannot happen. It contradicts the hypothesis that E-cadherin loss is the initial or primary cause for EMT. In conclusion, the results suggest that “E-cadherin transcriptional inactivation is an epi-phenomenon and part of an entire program, with much more severe effects than loss of E-cadherin expression alone”.[62] Other studies also show that epigenetic regulation of E-cadherin expression occurs during metastasis. The methylation patterns of the E-cadherin 5’ CpG island are not stable. During metastatic progression of many cases of epithelial tumors, a transient loss of E-cadherin is seen and the heterogeneous loss of E-cadherin expression results from a heterogeneous pattern of promoter region methylation of E-cadherin.[63]	https://www.wikidoc.org/index.php/CDH1_(gene)
5f9b832a0f4d32464b16a8c71951133dd14aaf67	wikidoc	CDH3 (gene)	CDH3 (gene) Cadherin-3, also known as P-Cadherin, is a protein that in humans is encoded by the CDH3 gene. # Function This gene is a classical cadherin from the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. This gene is located in a six-cadherin cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. In addition, aberrant expression of this protein is observed in cervical adenocarcinomas. # Clinical significance Mutations in this gene have been associated with congenital hypotrichosis with juvenile macular dystrophy. # Interactions CDH3 (gene) has been shown to interact with: - Beta-catenin, - CDH1, - Catenin (cadherin-associated protein), alpha 1, - Nephrin and - Plakoglobin.	CDH3 (gene) Cadherin-3, also known as P-Cadherin, is a protein that in humans is encoded by the CDH3 gene.[1][2] # Function This gene is a classical cadherin from the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. This gene is located in a six-cadherin cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. In addition, aberrant expression of this protein is observed in cervical adenocarcinomas. # Clinical significance Mutations in this gene have been associated with congenital hypotrichosis with juvenile macular dystrophy.[2] # Interactions CDH3 (gene) has been shown to interact with: - Beta-catenin,[3][4] - CDH1,[3] - Catenin (cadherin-associated protein), alpha 1,[3][4] - Nephrin[5] and - Plakoglobin.[3]	https://www.wikidoc.org/index.php/CDH3_(gene)
3b0167682264cda614712403fb006fee8c25cbec	wikidoc	Torcetrapib	Torcetrapib Torcetrapib (CP-529414) was a drug developed by Pfizer to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Its development was halted when the drug was associated with off target toxicity including an increase in blood pressure and adverse effects on the aldosterone axis. # Mechanism Torcetrapib is a cholesterylester transfer protein (CETP) inhibitor. This inhibition results in higher HDL cholesterol levels and reduces LDL cholesterol levels. Torcetrapib development began around 1990. The drug was first administered to humans in 1999. Manufacturing at production scale began in Ireland in 2005. # Development and research Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer's statin, atorvastatin (Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetraipib to be sold independently of Lipitor. A 2004 trial showed that torcetrapib could increase HDL and lower LDL with and without an added statin. # End of study On December 2 2006 Pfizer discontinued the pivotal phase III trial evaluating torcetrapib's safety and efficacy because of an increase in mortality and cardiovascular events associated with the drug's use. The cost of advancing the development of the drug to Phase III was over 800 million dollars.	Torcetrapib Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Torcetrapib (CP-529414) was a drug developed by Pfizer to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Its development was halted when the drug was associated with off target toxicity including an increase in blood pressure and adverse effects on the aldosterone axis. # Mechanism Torcetrapib is a cholesterylester transfer protein (CETP) inhibitor. This inhibition results in higher HDL cholesterol levels and reduces LDL cholesterol levels. Torcetrapib development began around 1990. The drug was first administered to humans in 1999. Manufacturing at production scale began in Ireland in 2005.[1] # Development and research Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer's statin, atorvastatin (Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetraipib to be sold independently of Lipitor.[2] A 2004 trial showed that torcetrapib could increase HDL and lower LDL with and without an added statin.[3] # End of study On December 2 2006 Pfizer discontinued the pivotal phase III trial evaluating torcetrapib's safety and efficacy because of an increase in mortality and cardiovascular events associated with the drug's use.[4] The cost of advancing the development of the drug to Phase III was over 800 million dollars.[5]	https://www.wikidoc.org/index.php/CETP_Inhibitors
a2da995036dc6c18a2b85f9ff65450aa89bb55c8	wikidoc	CHKB (gene)	CHKB (gene) Choline kinase beta (CK), also known as Ethanolamine kinase (EK), Choline kinase-like protein , choline/ethanolamine kinase beta (CKEKB), or Choline/ethanolamine kinase is a protein encoded by the CHKB gene. This gene is found on chromosome 22 in humans. The encoded protein plays a key role in phospholipid biosynthesis. Choline kinase (CK) and ethanolamine kinase (EK) catalyzes the first step in phosphatidylethanolamine biosynthesis. Read-through transcripts are expressed from this locus that include exons from the downstream CPT1B locus. # Structure The CHKB gene is located on the q arm of chromosome 22 at position 13.3 and it spans 4,041 base pairs. The CHKB gene produces a 7 kDa protein composed of 60 amino acids. The structure of the protein has been found to be a homodimer, and forms a heterodimer with the CHKA protein. It has also been found to contain multiple highly conserved domains, such as a Brenner phosphotransferase consensus sequence essential in catalytic function. # Function The CHKB gene encodes for a key protein in phospholipid biosynthesis. The choline kinase (CK) and ethanolamine kinase (EK) proteins, which are coded by the CHKB gene, catalyze the phosphorylation of choline/ethanolamine in vitro to phosphocholine/phosphoethanolamine. The catalysis is controlled by ATP in the presence of magnesium and ADP, and commits choline to the enzymatic pathway for biosynthesis of phosphatidylcholine. This is the first step in the biosynthesis of phosphocholine/phosphoethanolamine in all animal cells, and is done by the Kennedy pathway. The highly purified choline kinases from mammalian sources and their recombinant gene products have been shown to have ethanolamine kinase activity as well, indicating that both activities reside on the same protein. However, it has been shown that the protein has higher activity with ethanolamine and may not significantly contribute to in vivo phosphatidylcholine biosynthesis. The choline kinase-like protein encoded by CHKB belongs to the choline/ethanolamine kinase family; however, its exact function is not known. At least two transcript variants encoding two different isoforms have been found for this gene, and one of the transcripts is bicistronic. # Clinical significance Mutations in CHKB have been found to result in mitochondrial deficiencies and associated disorders. Knockdown of the gene has been known to result in decreased choline kinase and phosphatidylcholine activity. This impairment in activity may lead to a modified composition of the phospholipid composition in the mitochondrial membrane resulting in major disorders in the function and structure of the mitochondria. Major disorders include as Megaconial Congenital Muscular Dystrophy (MDCMC), and Narcolepsy. ## Megaconial Congenital Muscular Dystrophy (MDCMC) CHKB mutations have been majorly associated with Megaconial Congenital Muscular Dystrophy (MDCMC). Megaconial Congenital Muscular Dystrophy (MDCMC) is an autosomal recessive congenital muscular muscular dystrophy characterized by muscle biopsy results displaying an enlarged mitochondria which are common in the periphery of the fibers but scarce around the center. Common clinical manifestations of MDCMC include: - early-onset hypotonia - muscle wasting - mildly elevated serum creatine kinase (CK) levels - severe intellectual disability without brain structural abnormalities - Gower's sign - mental retardation - fatal cardiomyopathy Symptoms such as neurogenic atrophy, enlarged mitochondria in the periphery of the fibers, and complex I deficiency were shown in a Spanish patient with a homozygous mutation of c.810T>A. Another patient with a homozygous mutation (p.E292X) in the CHKB gene exhibited rhythmic jerkings of arms, which were characterized as muscle spasms. Finally, a patient with a homozygous c.810T>A showed signs of Gower's sign, hypotonia, and proximal muscle weakness. ## Narcolepsy Narcolepsy is a neurological disabling sleep disorder, characterized by excessive daytime sleepiness, sleep fragmentation, symptoms of abnormal rapid-eye-movement (REM) sleep, cataplexy, hypnagogic hallucinations, and sleep paralysis. Cataplexy is a sudden loss of muscle tone triggered by emotions, which is the most valuable clinical feature used to diagnose narcolepsy. Human narcolepsy is primarily a sporadically occurring disorder but familial clustering has been observed. # Interactions CHKB has been shown to have Protein-protein interactions with the following. - ALB - Human serum albumin	CHKB (gene) Choline kinase beta (CK), also known as Ethanolamine kinase (EK), Choline kinase-like protein , choline/ethanolamine kinase beta (CKEKB), or Choline/ethanolamine kinase is a protein encoded by the CHKB gene.[1][2] This gene is found on chromosome 22 in humans. The encoded protein plays a key role in phospholipid biosynthesis. Choline kinase (CK) and ethanolamine kinase (EK) catalyzes the first step in phosphatidylethanolamine biosynthesis. Read-through transcripts are expressed from this locus that include exons from the downstream CPT1B locus.[3][4][5] # Structure The CHKB gene is located on the q arm of chromosome 22 at position 13.3 and it spans 4,041 base pairs.[3] The CHKB gene produces a 7 kDa protein composed of 60 amino acids.[6][7] The structure of the protein has been found to be a homodimer, and forms a heterodimer with the CHKA protein.[5][4] It has also been found to contain multiple highly conserved domains, such as a Brenner phosphotransferase consensus sequence essential in catalytic function.[8] # Function The CHKB gene encodes for a key protein in phospholipid biosynthesis. The choline kinase (CK) and ethanolamine kinase (EK) proteins, which are coded by the CHKB gene, catalyze the phosphorylation of choline/ethanolamine in vitro to phosphocholine/phosphoethanolamine. The catalysis is controlled by ATP in the presence of magnesium and ADP, and commits choline to the enzymatic pathway for biosynthesis of phosphatidylcholine. This is the first step in the biosynthesis of phosphocholine/phosphoethanolamine in all animal cells, and is done by the Kennedy pathway. The highly purified choline kinases from mammalian sources and their recombinant gene products have been shown to have ethanolamine kinase activity as well, indicating that both activities reside on the same protein. However, it has been shown that the protein has higher activity with ethanolamine and may not significantly contribute to in vivo phosphatidylcholine biosynthesis. The choline kinase-like protein encoded by CHKB belongs to the choline/ethanolamine kinase family; however, its exact function is not known. At least two transcript variants encoding two different isoforms have been found for this gene, and one of the transcripts is bicistronic.[3][4][5][9][10] # Clinical significance Mutations in CHKB have been found to result in mitochondrial deficiencies and associated disorders. Knockdown of the gene has been known to result in decreased choline kinase and phosphatidylcholine activity. This impairment in activity may lead to a modified composition of the phospholipid composition in the mitochondrial membrane resulting in major disorders in the function and structure of the mitochondria. Major disorders include as Megaconial Congenital Muscular Dystrophy (MDCMC), and Narcolepsy.[3][11] ## Megaconial Congenital Muscular Dystrophy (MDCMC) CHKB mutations have been majorly associated with Megaconial Congenital Muscular Dystrophy (MDCMC). Megaconial Congenital Muscular Dystrophy (MDCMC) is an autosomal recessive congenital muscular muscular dystrophy characterized by muscle biopsy results displaying an enlarged mitochondria which are common in the periphery of the fibers but scarce around the center.[12] Common clinical manifestations of MDCMC include:[11][13] - early-onset hypotonia - muscle wasting - mildly elevated serum creatine kinase (CK) levels - severe intellectual disability without brain structural abnormalities - Gower's sign - mental retardation - fatal cardiomyopathy Symptoms such as neurogenic atrophy, enlarged mitochondria in the periphery of the fibers, and complex I deficiency were shown in a Spanish patient with a homozygous mutation of c.810T>A.[11] Another patient with a homozygous mutation (p.E292X) in the CHKB gene exhibited rhythmic jerkings of arms, which were characterized as muscle spasms.[10] Finally, a patient with a homozygous c.810T>A showed signs of Gower's sign, hypotonia, and proximal muscle weakness.[14] ## Narcolepsy Narcolepsy is a neurological disabling sleep disorder, characterized by excessive daytime sleepiness, sleep fragmentation, symptoms of abnormal rapid-eye-movement (REM) sleep, cataplexy, hypnagogic hallucinations, and sleep paralysis. Cataplexy is a sudden loss of muscle tone triggered by emotions, which is the most valuable clinical feature used to diagnose narcolepsy. Human narcolepsy is primarily a sporadically occurring disorder but familial clustering has been observed.[15] # Interactions CHKB has been shown to have Protein-protein interactions with the following.[16][4] - ALB - Human serum albumin	https://www.wikidoc.org/index.php/CHKB_(gene)
66f3838d0608e65162f4eaf74b27bd2d0608e8d5	wikidoc	CHML (gene)	CHML (gene) Rab proteins geranylgeranyltransferase component A 2 is an enzyme that in humans is encoded by the CHML gene. The product of the CHML gene supports geranylgeranylation of most Rab proteins and may substitute for REP-1 in tissues other than retina. CHML is localized close to the gene for Usher syndrome type II. # Interactions CHML (gene) has been shown to interact with RAB1A and RAB5A.	CHML (gene) Rab proteins geranylgeranyltransferase component A 2 is an enzyme that in humans is encoded by the CHML gene.[1][2] The product of the CHML gene supports geranylgeranylation of most Rab proteins and may substitute for REP-1 in tissues other than retina. CHML is localized close to the gene for Usher syndrome type II.[2] # Interactions CHML (gene) has been shown to interact with RAB1A[3][4] and RAB5A.[3][4]	https://www.wikidoc.org/index.php/CHML_(gene)
5f52a1c5c9a379b25760cd35d2f8c4a89437f755	wikidoc	CJP Sandbox	CJP Sandbox $(document).ready(loadResources); function loadResources() { jQuery.browser = {}; (function () { jQuery.browser.msie = false; jQuery.browser.version = 0; if (navigator.userAgent.match(/MSIE (+)\./)) { jQuery.browser.msie = true; jQuery.browser.version = RegExp.$1; // mw.loader.load('mediaWiki.user'); $('#search').click(runQuery); $('#query-container').change(updateDisplay); $('#update').click(updateDisplay); $("#slider").slider({ min: 0, max: 25, step: 1, range: true, values: , slide: function(event, ui) { if (ui.values < ui.values) $("input.pillSizeSlider").val(ui.values); $("input.pillSizeSlider").val(ui.values); updatePillSizeImages(); else if (ui.values > ui.values) $("input.pillSizeSlider").val(ui.values); $("input.pillSizeSlider").val(ui.values); updatePillSizeImages(); else $("input.pillSizeSlider").val(ui.values); $("input.pillSizeSlider").val(ui.values); updatePillSizeImages(); $('input.pillSizeSlider').val($("#slider").slider("option","values")); $('input.pillSizeSlider').val($("#slider").slider("option","values")); $("input.pillSizeSlider").change(function() { var $this = $(this); $("#slider").slider("values", $this.data("index"), $this.val()); updatePillSizeImages(); function updatePillSizeImages() { var minPillSize = $('input.pillSizeSlider').val(); var maxPillSize = $('input.pillSizeSlider').val(); var pillArr = [ $("#queryDisplaySmallSize").attr("src",pillArr); $("#queryDisplayLargeSize").attr("src",pillArr); function buildQueryParameters(){ var queryShape = ""; var queryColor = ""; var queryScoring = ""; var queryImprint = ""; var queryMinSize = ""; var queryMaxSize = ""; var queryNDC = ""; var queryIngred = ""; if (document.getElementById('selectedShape').value) var queryShape = ']'; if (document.getElementById('selectedColor').value) var queryColor = ']' if (document.getElementById('selectedScoring').value) var queryScoring = ']' if (document.getElementById('selectedImprint').value) var queryImprint = ']' if (document.getElementById('selectedMinSize').value) var queryMinSize = ']' if (document.getElementById('selectedMaxSize').value) var queryMaxSize = ']' if (document.getElementById('selectedNDC').value) var queryNDC = ']' if (document.getElementById('selectedIngred').value) var selectedIngredArray = document.getElementById('selectedIngred').value.split(','); $.each(selectedIngredArray, function(index, value){ selectedIngredArray = ']'; var queryIngred = selectedIngredArray.join(""); return queryShape+queryColor+queryScoring+queryImprint+queryMinSize+queryMaxSize+queryNDC+queryIngred; function updateDisplay() { if (document.getElementById('selectedShape').value) switch(document.getElementById('selectedShape').value){ case "Round": document.getElementById('queryDisplayShape').src = ""; break; case "Oval": document.getElementById('queryDisplayShape').src = ""; break; case "Square": document.getElementById('queryDisplayShape').src = ""; break; case "Rectangular": document.getElementById('queryDisplayShape').src = ""; break; case "Triangular": document.getElementById('queryDisplayShape').src = ""; break; case "Capsule": document.getElementById('queryDisplayShape').src = ""; break; case "Pentagon": document.getElementById('queryDisplayShape').src = ""; break; case "Hexagon": document.getElementById('queryDisplayShape').src = ""; break; case "Diamond": document.getElementById('queryDisplayShape').src = ""; break; case "Gear": document.getElementById('queryDisplayShape').src = ""; break; case "DoubleCircle": document.getElementById('queryDisplayShape').src = ""; break; case "Clover": document.getElementById('queryDisplayShape').src = ""; break; case "TearDrop": document.getElementById('queryDisplayShape').src = ""; break; case "Octagon": document.getElementById('queryDisplayShape').src = ""; break; case "SemiCircle": document.getElementById('queryDisplayShape').src = ""; break; case "Bullet": document.getElementById('queryDisplayShape').src = ""; break; case "Trapezoid": document.getElementById('queryDisplayShape').src = ""; break; case "FreeForm": document.getElementById('queryDisplayShape').src = ""; break; if (document.getElementById('selectedImprint').value) document.getElementById('queryDisplaySelectedImprint').innerHTML = document.getElementById('selectedImprint').value function changeImage(a) { document.getElementById("img").src=a; function runQuery() { $('#resultsTable-body tr').remove(); var queryParameters = buildQueryParameters(); var printoutRequests = "\|?Pill%20Imprint\|?Pill%20Dosage\|?Pill%20Ingred\|?Pill%20Color\|?Pill%20Shape\|?Pill%20Size%20(mm)\|?Pill%20Scoring\|?NDC\|?Pill%20Name"; var jsonURL = "="+queryParameters+printoutRequests+"&format=json" $.getJSON(jsonURL, function (data) { $.each(data.query.results, function(ind, val) { ////// Store each returned result ////// //If the .getJSON() function is able to successfully receive information //from the WikiDoc API, it will begin to execute the unnamed function we //have provided. The data that is returned is in JSON format, meaning //that we will have lots of objects within objects. Our function says //that for EACH property of data.query.results (that is, each returned //result from the query) we should perform the following operations. //We will first store all the results as local variables. Some of these //results will need to be converted to a string, so don't be alarmed if //you see some string() methods. After storing our variables,we //construct a hyperlink and image URL. Lastly, we add a row to the //our results table. //The EACH loop will run through all of the described steps before //starting with the next returned result. Doing this will build a table //of our results, row by row. drugNameFull = val.fulltext; drugNameShort = drugNameFull.split("#"); pillImprint = val.printouts; pillDosage = val.printouts; pillIngred = val.printouts; pillColor = val.printouts; pillShape = val.printouts; pillSize = val.printouts; pillScoring = val.printouts; ndc = val.printouts; pillName = String(val.printouts).split(' ').join('_'); ////// Generate the URL to the image. ////// //When a picture is uploaded, the server will place the file in a //directory. This directory is based upon the MD5 hashed name of file. A //file named "Example.jpg" will have an MD5 hashed name of: // "a91fe217e45a700fc2dab0cc476f01c7." //The file would then be located at the following URl: //To generate the URL, we use the MD5 method provided in the CryptoJS lib //This means must be loaded //First we create the MD5 hash of the pill name md5 = String(CryptoJS.MD5(pillName)); //Next we build the directory name using the first two characters imageDirect = '/' + md5.charAt(0) + '/' + md5.substring(0,2) + '/' + pillName ////// Create the Drug Name Hyperlink ////// //Turn the spaces into underscores linkName = String(drugNameShort).split(' ').join('_') //String together appropiate text to create the link drugNameLink = ''+drugNameShort+'' ////// Add each iteration of query results to the Results Table ////// //Adding the results parameters works in the following way. // The location of a specific table within the document is assigned to // the variable "table" // A row is added the to table at the index location (ind being the // index of the .each() loop. // Cells are then added to each row with a named corresponding to the // column header. For example, Drug Name is the header of the first // column, so the cell in the 0 index (the first cell of the row) will // have a variable name of cellDrugName // The cells are then populated with //Find a element with id="resultsTable-body": table = document.getElementById("resultsTable-body"); //Create an empty element and add it to the 1st position of the table: row = table.insertRow(ind); //Insert new cells( elements) into the "new" element: cellDrugName = row.insertCell(0); cellPillImprint = row.insertCell(1); cellPillDosage = row.insertCell(2); cellPillIngred = row.insertCell(3); cellPillColor = row.insertCell(4); cellPillShape = row.insertCell(5); cellPillSize = row.insertCell(6); cellPillSocring = row.insertCell(7); cellNDC = row.insertCell(8); cellPillName = row.insertCell(9); //Add Values to the cells: cellDrugName.innerHTML = drugNameLink; cellPillImprint.innerHTML = pillImprint; cellPillDosage.innerHTML = pillDosage; cellPillIngred.innerHTML = pillIngred; cellPillColor.innerHTML = pillColor; cellPillShape.innerHTML = pillShape; cellPillSize.innerHTML = pillSize; cellPillSocring.innerHTML = pillScoring; cellNDC.innerHTML = ndc; cellPillName.innerHTML = ''; $('#resultsTable-container').css("visibility", "visible") /Query Container Query Container The Query Container is a container which holds both the propertyToolbar and the queryDisplay. #query-container{ width:100%; position:relative; /Query Builder/ #queryBuilder-container{ background-color:#B0E0E6; width:100%; position:relative; vertical-align:middle; clear:both; padding:0.5%; #queryBuilder-container div{ width:15%; background-color:#B0E0E6; margin-left:0.5%; margin-right:0.5%; margin-top:10px; margin-bottom:10px; display:inline-block; vertical-align:middle; align-content:center; overflow:hidden; #queryBuilder-container div img{ height:100%; width:auto; display:block; margin:auto; .queryDisplayHeader{ position:relative; width:100% !important; text-align:center; margin:0px !important; padding-top:0.5em; font-family: sans-serif, "Chrysanthi Unicode", "Doulos SIL", Gentium, GentiumAlt, Code2000, "TITUS Cyberbit Basic", "DejaVu Sans", "Bitstream Cyberbit", "Arial Unicode MS", "Lucida Sans Unicode", "Hiragino Kaku Gothic Pro", "Matrix Unicode"; .queryDisplayContent{ positon:relative; width:100% !important; vertical-align:top; margin:0px !important; #queryDisplayShape{ width:118px !important; height:auto !important; #queryDisplayScore{ width:80% !important; height:auto !important; #queryDisplayColor-1{ width:118px !important; height:auto !important; #queryDisplaySize{ width:118px !important; height:auto !important; #queryDisplayContent img{ height:44px !important; float:right !important; /Results* Results Table Contains style attributes for the following elements: -#resultsTable-container -#resultsTable -.resultsTable-class including th and tr #resultsTable-container{ width:100% !important; position:relative; #resultsTable{ border-collapse:collapse; width:100% !important; table-layout:fixed; border:1px solid #B0E0E6; margin:10px; .resultsTable-class th{ background-color:#B0E0E6; padding:5px; width:125px; height:25px; .resultsTable-class tbody tr:nth-child(even){ background-color:#EBEDED; text-align:center; .resultsTable-class tbody tr:nth-child(odd){ background-color:#FFFFFF; text-align:center; .resultsTable-class tbody img{ width:300px !important; #propertyToolbar-container{ background-color:#B0E0E6; width:100%; display:block; #selectedShape{ width:120px; #propertyShapeColor-container, #propertyScoringImprint-container, #propertySize-container, #propertyNDCIngreds-container{ Display:inline-block;	CJP Sandbox $(document).ready(loadResources); function loadResources() { jQuery.browser = {}; (function () { jQuery.browser.msie = false; jQuery.browser.version = 0; if (navigator.userAgent.match(/MSIE ([0-9]+)\./)) { jQuery.browser.msie = true; jQuery.browser.version = RegExp.$1; } })(); // mw.loader.load('mediaWiki.user'); $('#search').click(runQuery); $('#query-container').change(updateDisplay); $('#update').click(updateDisplay); $("#slider").slider({ min: 0, max: 25, step: 1, range: true, values: [5, 20], slide: function(event, ui) { if (ui.values[0] < ui.values[1]) { $("input.pillSizeSlider[data-index=0]").val(ui.values[0]); $("input.pillSizeSlider[data-index=1]").val(ui.values[1]); updatePillSizeImages(); } else if (ui.values[0] > ui.values[1]) { $("input.pillSizeSlider[data-index=1]").val(ui.values[0]); $("input.pillSizeSlider[data-index=0]").val(ui.values[1]); updatePillSizeImages(); } else { $("input.pillSizeSlider[data-index=0]").val(ui.values[0]); $("input.pillSizeSlider[data-index=1]").val(ui.values[1]); updatePillSizeImages(); } } }); $('input.pillSizeSlider[data-index=0]').val($("#slider").slider("option","values")[0]); $('input.pillSizeSlider[data-index=1]').val($("#slider").slider("option","values")[1]); $("input.pillSizeSlider").change(function() { var $this = $(this); $("#slider").slider("values", $this.data("index"), $this.val()); updatePillSizeImages(); }); }; function updatePillSizeImages() { var minPillSize = $('input.pillSizeSlider[data-index=0]').val(); var maxPillSize = $('input.pillSizeSlider[data-index=1]').val(); var pillArr = [ "http://static.wikidoc.org/3/35/Pill_Size_1_mm.png", "http://static.wikidoc.org/3/35/Pill_Size_1_mm.png", "http://static.wikidoc.org/8/8a/Pill_Size_2_mm.png", "http://static.wikidoc.org/f/f7/Pill_Size_3_mm.png", "http://static.wikidoc.org/f/fb/Pill_Size_4_mm.png", "http://static.wikidoc.org/f/f2/Pill_Size_5_mm.png", "http://static.wikidoc.org/d/d8/Pill_Size_6_mm.png", "http://static.wikidoc.org/e/ec/Pill_Size_7_mm.png", "http://static.wikidoc.org/4/4d/Pill_Size_8_mm.png", "http://static.wikidoc.org/9/97/Pill_Size_9_mm.png", "http://static.wikidoc.org/3/36/Pill_Size_10_mm.png", "http://static.wikidoc.org/2/2e/Pill_Size_11_mm.png", "http://static.wikidoc.org/c/c5/Pill_Size_12_mm.png", "http://static.wikidoc.org/0/0d/Pill_Size_13_mm.png", "http://static.wikidoc.org/1/16/Pill_Size_14_mm.png", "http://static.wikidoc.org/4/4a/Pill_Size_15_mm.png", "http://static.wikidoc.org/e/ee/Pill_Size_16_mm.png", "http://static.wikidoc.org/8/86/Pill_Size_17_mm.png", "http://static.wikidoc.org/a/af/Pill_Size_18_mm.png", "http://static.wikidoc.org/e/ea/Pill_Size_19_mm.png", "http://static.wikidoc.org/e/e6/Pill_Size_20_mm.png", "http://static.wikidoc.org/e/e2/Pill_Size_21_mm.png", "http://static.wikidoc.org/a/a3/Pill_Size_22_mm.png", "http://static.wikidoc.org/b/b4/Pill_Size_23_mm.png", "http://static.wikidoc.org/c/cf/Pill_Size_24_mm.png", "http://static.wikidoc.org/9/92/Pill_Size_25_mm.png" ]; $("#queryDisplaySmallSize").attr("src",pillArr[minPillSize]); $("#queryDisplayLargeSize").attr("src",pillArr[maxPillSize]); }; function buildQueryParameters(){ var queryShape = ""; var queryColor = ""; var queryScoring = ""; var queryImprint = ""; var queryMinSize = ""; var queryMaxSize = ""; var queryNDC = ""; var queryIngred = ""; if (document.getElementById('selectedShape').value) { var queryShape = '[[Pill%20Shape::' + document.getElementById('selectedShape').value + ']]'; } if (document.getElementById('selectedColor').value) { var queryColor = '[[Pill%20Color::' + document.getElementById('selectedColor').value + ']]' } if (document.getElementById('selectedScoring').value) { var queryScoring = '[[Pill%20Scoring::' + document.getElementById('selectedScoring').value + ']]' } if (document.getElementById('selectedImprint').value) { var queryImprint = '[[Pill%20Imprint::' + document.getElementById('selectedImprint').value + ']]' } if (document.getElementById('selectedMinSize').value) { var queryMinSize = '[[Pill%20Size%20(mm)::>' + document.getElementById('selectedMinSize').value + ']]' } if (document.getElementById('selectedMaxSize').value) { var queryMaxSize = '[[Pill%20Size%20(mm)::<' + document.getElementById('selectedMaxSize').value + ']]' } if (document.getElementById('selectedNDC').value) { var queryNDC = '[[NDC::' + document.getElementById('selectedNDC').value + ']]' } if (document.getElementById('selectedIngred').value) { var selectedIngredArray = document.getElementById('selectedIngred').value.split(','); $.each(selectedIngredArray, function(index, value){ selectedIngredArray[index] = '[[Pill%20Ingred::' + value.trim() + ']]'; }); var queryIngred = selectedIngredArray.join(""); } return queryShape+queryColor+queryScoring+queryImprint+queryMinSize+queryMaxSize+queryNDC+queryIngred; }; function updateDisplay() { if (document.getElementById('selectedShape').value) { switch(document.getElementById('selectedShape').value){ case "Round": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/7/79/Round_Grey_Pill.png"; break; case "Oval": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/3/3d/Oval_Grey_Pill.png"; break; case "Square": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/e/e9/Square_Grey_Pill.png"; break; case "Rectangular": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/8/8e/Rectangular_Grey_Pill.png"; break; case "Triangular": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/c/cb/Triangular_Grey_Pill.png"; break; case "Capsule": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/b/b8/Capsule_Grey_Pill.png"; break; case "Pentagon": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/b/be/Pentagon_Grey_Pill.png"; break; case "Hexagon": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/2/25/Hexagon_Grey_Pill.png"; break; case "Diamond": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/9/98/Diamond_Grey_Pill.png"; break; case "Gear": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/5/56/Gear_Grey_Pill.png"; break; case "DoubleCircle": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/7/73/Double_Circle_Grey_Pill.png"; break; case "Clover": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/a/a3/Clover_Grey_Pill.png"; break; case "TearDrop": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/9/9a/Tear_Drop_Grey_Pill.png"; break; case "Octagon": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/f/f7/Octagon_Grey_Pill.png"; break; case "SemiCircle": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/8/80/SemiCircle_Grey_Pill.png"; break; case "Bullet": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/8/8c/Bullet_Grey_Pill.png"; break; case "Trapezoid": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/7/7a/Trapezoid_Grey_Pill.png"; break; case "FreeForm": document.getElementById('queryDisplayShape').src = "http://www.wikidoc.org/images/f/fa/Free_Form_Grey_Pill.png"; break; } } if (document.getElementById('selectedImprint').value) { document.getElementById('queryDisplaySelectedImprint').innerHTML = document.getElementById('selectedImprint').value } }; function changeImage(a) { document.getElementById("img").src=a; } function runQuery() { $('#resultsTable-body tr').remove(); var queryParameters = buildQueryParameters(); var printoutRequests = "\|?Pill%20Imprint\|?Pill%20Dosage\|?Pill%20Ingred\|?Pill%20Color\|?Pill%20Shape\|?Pill%20Size%20(mm)\|?Pill%20Scoring\|?NDC\|?Pill%20Name"; var jsonURL = "http://www.wikidoc.org/api.php?action=ask&query="+queryParameters+printoutRequests+"&format=json" $.getJSON(jsonURL, function (data) { $.each(data.query.results, function(ind, val) { ///////////////////////////////////////////////////////////////////////// ////// Store each returned result ////// ///////////////////////////////////////////////////////////////////////// // //If the .getJSON() function is able to successfully receive information //from the WikiDoc API, it will begin to execute the unnamed function we //have provided. The data that is returned is in JSON format, meaning //that we will have lots of objects within objects. Our function says //that for EACH property of data.query.results (that is, each returned //result from the query) we should perform the following operations. // //We will first store all the results as local variables. Some of these //results will need to be converted to a string, so don't be alarmed if //you see some string() methods. After storing our variables,we //construct a hyperlink and image URL. Lastly, we add a row to the //our results table. // //The EACH loop will run through all of the described steps before //starting with the next returned result. Doing this will build a table //of our results, row by row. drugNameFull = val.fulltext; drugNameShort = drugNameFull.split("#")[0]; pillImprint = val.printouts["Pill Imprint"]; pillDosage = val.printouts["Pill Dosage"]; pillIngred = val.printouts["Pill Ingred"]; pillColor = val.printouts["Pill Color"]; pillShape = val.printouts["Pill Shape"]; pillSize = val.printouts["Pill Size (mm)"]; pillScoring = val.printouts["Pill Scoring"]; ndc = val.printouts["NDC"]; pillName = String(val.printouts["Pill Name"][0]).split(' ').join('_'); ///////////////////////////////////////////////////////////////////////// ////// Generate the URL to the image. ////// ///////////////////////////////////////////////////////////////////////// // //When a picture is uploaded, the server will place the file in a //directory. This directory is based upon the MD5 hashed name of file. A //file named "Example.jpg" will have an MD5 hashed name of: // "a91fe217e45a700fc2dab0cc476f01c7." //The file would then be located at the following URl: // "http://static.wikidoc.org/a/a9/Example.jpg" //To generate the URL, we use the MD5 method provided in the CryptoJS lib //This means http://www.wikidoc.org/includes/raty/md5.js must be loaded //First we create the MD5 hash of the pill name md5 = String(CryptoJS.MD5(pillName)); //Next we build the directory name using the first two characters imageDirect = 'http://static.wikidoc.org/' + md5.charAt(0) + '/' + md5.substring(0,2) + '/' + pillName ///////////////////////////////////////////////////////////////////////// ////// Create the Drug Name Hyperlink ////// ///////////////////////////////////////////////////////////////////////// //Turn the spaces into underscores linkName = String(drugNameShort).split(' ').join('_') //String together appropiate text to create the link drugNameLink = '<a href="http://www.wikidoc.org/index.php/'+linkName+'">'+drugNameShort+'</a>' ///////////////////////////////////////////////////////////////////////// ////// Add each iteration of query results to the Results Table ////// ///////////////////////////////////////////////////////////////////////// // //Adding the results parameters works in the following way. // The location of a specific table within the document is assigned to // the variable "table" // // A row is added the to table at the index location (ind being the // index of the .each() loop. // // Cells are then added to each row with a named corresponding to the // column header. For example, Drug Name is the header of the first // column, so the cell in the 0 index (the first cell of the row) will // have a variable name of cellDrugName // // The cells are then populated with //Find a <table> element with id="resultsTable-body": table = document.getElementById("resultsTable-body"); //Create an empty <tr> element and add it to the 1st position of the table: row = table.insertRow(ind); //Insert new cells(<td> elements) into the "new" <tr> element: cellDrugName = row.insertCell(0); cellPillImprint = row.insertCell(1); cellPillDosage = row.insertCell(2); cellPillIngred = row.insertCell(3); cellPillColor = row.insertCell(4); cellPillShape = row.insertCell(5); cellPillSize = row.insertCell(6); cellPillSocring = row.insertCell(7); cellNDC = row.insertCell(8); cellPillName = row.insertCell(9); //Add Values to the cells: cellDrugName.innerHTML = drugNameLink; cellPillImprint.innerHTML = pillImprint; cellPillDosage.innerHTML = pillDosage; cellPillIngred.innerHTML = pillIngred; cellPillColor.innerHTML = pillColor; cellPillShape.innerHTML = pillShape; cellPillSize.innerHTML = pillSize; cellPillSocring.innerHTML = pillScoring; cellNDC.innerHTML = ndc; cellPillName.innerHTML = '<img class="pillImages" src="' + imageDirect + '" />'; }); }); $('#resultsTable-container').css("visibility", "visible") }; /Query Container***************************************** ****** Query Container ****** ********************************************************* The Query Container is a container which holds both the propertyToolbar and the queryDisplay. **********************************************************/ #query-container{ width:100%; position:relative; } /Query Builder/ #queryBuilder-container{ background-color:#B0E0E6; width:100%; position:relative; vertical-align:middle; clear:both; padding:0.5%; } #queryBuilder-container div{ width:15%; background-color:#B0E0E6; margin-left:0.5%; margin-right:0.5%; margin-top:10px; margin-bottom:10px; display:inline-block; vertical-align:middle; align-content:center; overflow:hidden; } #queryBuilder-container div img{ height:100%; width:auto; display:block; margin:auto; } .queryDisplayHeader{ position:relative; width:100% !important; text-align:center; margin:0px !important; padding-top:0.5em; font-family: sans-serif, "Chrysanthi Unicode", "Doulos SIL", Gentium, GentiumAlt, Code2000, "TITUS Cyberbit Basic", "DejaVu Sans", "Bitstream Cyberbit", "Arial Unicode MS", "Lucida Sans Unicode", "Hiragino Kaku Gothic Pro", "Matrix Unicode"; } .queryDisplayContent{ positon:relative; width:100% !important; vertical-align:top; margin:0px !important; } #queryDisplayShape{ width:118px !important; height:auto !important; } #queryDisplayScore{ width:80% !important; height:auto !important; } #queryDisplayColor-1{ width:118px !important; height:auto !important; } #queryDisplaySize{ width:118px !important; height:auto !important; } #queryDisplayContent img{ height:44px !important; float:right !important; } /Results*************************************************** ****** Results Table ****** ********************************************************** ********************************************************** Contains style attributes for the following elements: -#resultsTable-container -#resultsTable -.resultsTable-class including th and tr ********************************************************** ***********************************************************/ #resultsTable-container{ width:100% !important; position:relative; } #resultsTable{ border-collapse:collapse; width:100% !important; table-layout:fixed; border:1px solid #B0E0E6; margin:10px; } .resultsTable-class th{ background-color:#B0E0E6; padding:5px; width:125px; height:25px; } .resultsTable-class tbody tr:nth-child(even){ background-color:#EBEDED; text-align:center; } .resultsTable-class tbody tr:nth-child(odd){ background-color:#FFFFFF; text-align:center; } .resultsTable-class tbody img{ width:300px !important; } #propertyToolbar-container{ background-color:#B0E0E6; width:100%; display:block; } #selectedShape{ width:120px; } #propertyShapeColor-container, #propertyScoringImprint-container, #propertySize-container, #propertyNDCIngreds-container{ Display:inline-block; }	https://www.wikidoc.org/index.php/CJP_Sandbox
534e638a302aa7e3d2736177fff46bd33a0c50da	wikidoc	CKLF (gene)	CKLF (gene) Chemokine-like factor is a protein that in humans is encoded by the CKLF gene. The product of this gene is a cytokine. Cytokines are small proteins that have an essential role in the immune and inflammatory responses. This gene is one of several chemokine-like factor genes located in a cluster on chromosome 16. The protein encoded by this gene is a potent chemoattractant for neutrophils, monocytes and lymphocytes. It also can stimulate the proliferation of skeletal muscle cells. This protein may play important roles in inflammation and in the regeneration of skeletal muscle. Alternatively spliced transcript variants encoding different isoforms have been identified.	CKLF (gene) Chemokine-like factor is a protein that in humans is encoded by the CKLF gene.[1][2][3] The product of this gene is a cytokine. Cytokines are small proteins that have an essential role in the immune and inflammatory responses. This gene is one of several chemokine-like factor genes located in a cluster on chromosome 16. The protein encoded by this gene is a potent chemoattractant for neutrophils, monocytes and lymphocytes. It also can stimulate the proliferation of skeletal muscle cells. This protein may play important roles in inflammation and in the regeneration of skeletal muscle. Alternatively spliced transcript variants encoding different isoforms have been identified.[3]	https://www.wikidoc.org/index.php/CKLF_(gene)
917c02826789fa9cd16d42ba34bc9ac54f1fb942	wikidoc	Hypercarbia	Hypercarbia # Overview Hypercarbia means to have more than normal CO2 (Carbon dioxide) levels in the blood. # Pathophysiology - Value is usually obtained while performing a basic Chem-7 blood test, which tests for basic electrolyte levels from a blood sample. - Normal values of CO2 for anyone over 2 years of age is between 22 and 26 mmol/L. - Increased levels of serum CO2 are found in some disease processes such as COPD and emphysema and is related to the lung's decreased capacity for effective gas exchange. - Hypercarbia has been used to induce NDE-like experiences in patients, and to treat mental disorders. - VA = (VT-VD) X breaths/min is a formula that can calculate ventilation in the alveolar (VA). # Causes - Hypercarbia can be caused by decreased tidal volume (VT), increased dead space (VD), or decreased breaths per minute. # Related Chapters - Hypercapnia - Respiratory system	Hypercarbia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hypercarbia means to have more than normal CO2 (Carbon dioxide) levels in the blood. # Pathophysiology - Value is usually obtained while performing a basic Chem-7 blood test, which tests for basic electrolyte levels from a blood sample. - Normal values of CO2 for anyone over 2 years of age is between 22 and 26 mmol/L. - Increased levels of serum CO2 are found in some disease processes such as COPD and emphysema and is related to the lung's decreased capacity for effective gas exchange. - Hypercarbia has been used to induce NDE-like experiences in patients, and to treat mental disorders. - VA = (VT-VD) X breaths/min is a formula that can calculate ventilation in the alveolar (VA). # Causes - Hypercarbia can be caused by decreased tidal volume (VT), increased dead space (VD), or decreased breaths per minute. # Related Chapters - Hypercapnia - Respiratory system Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/CO2_retention
505a05e44d0c29deea2c35746a97a28731dffb8c	wikidoc	COPA (gene)	COPA (gene) Coatomer subunit alpha is a protein that in humans is encoded by the COPA gene. # Function In eukaryotic cells, protein transport between the endoplasmic reticulum and Golgi compartments is mediated in part by non-clathrin-coated vesicular coat proteins (COPs). Seven coat proteins have been identified, and they represent subunits of a complex known as coatomer. The subunits are designated alpha-COP, beta-COP, beta-prime-COP, gamma-COP, delta-COP, epsilon-COP, and zeta-COP. The alpha-COP, encoded by COPA, shares high sequence similarity with RET1P, the alpha subunit of the coatomer complex in yeast. Also, the N-terminal 25 amino acids of alpha-COP encode the bioactive peptide, xenin, which stimulates exocrine pancreatic secretion and may act as a gastrointestinal hormone. Alternative splicing results in multiple splice forms encoding distinct isoforms. # Interactions COPA (gene) has been shown to interact with COPE and COPB1.	COPA (gene) Coatomer subunit alpha is a protein that in humans is encoded by the COPA gene.[1][2] # Function In eukaryotic cells, protein transport between the endoplasmic reticulum and Golgi compartments is mediated in part by non-clathrin-coated vesicular coat proteins (COPs). Seven coat proteins have been identified, and they represent subunits of a complex known as coatomer. The subunits are designated alpha-COP, beta-COP, beta-prime-COP, gamma-COP, delta-COP, epsilon-COP, and zeta-COP. The alpha-COP, encoded by COPA, shares high sequence similarity with RET1P, the alpha subunit of the coatomer complex in yeast.[3] Also, the N-terminal 25 amino acids of alpha-COP encode the bioactive peptide, xenin, which stimulates exocrine pancreatic secretion and may act as a gastrointestinal hormone. Alternative splicing results in multiple splice forms encoding distinct isoforms.[2] # Interactions COPA (gene) has been shown to interact with COPE[4][5][6] and COPB1.[7]	https://www.wikidoc.org/index.php/COPA_(gene)
0228ca8f4ff74d12163f389008f8ed37c1ecb1df	wikidoc	CTNS (gene)	CTNS (gene) CTNS may also refer to the Center for Theology and the Natural Sciences. CTNS is the gene that encodes the protein cystinosin in humans. Cystinosin is a lysosomal seven-transmembrane protein that functions as an active transporter for the export of cystine molecules out of the lysosome. Mutations in CTNS are responsible for cystinosis, an autosomal recessive lysosomal storage disease. # Discovery In 1995, the gene was localized to the short arm of chromosome 17. An international collaborative effort finally succeeded in isolating CTNS by positional cloning in 1998. # Gene CTNS is located on the p arm of human chromosome 17, at position 13.2. It spans base pairs 3,636,468 and 3,661,542, and comprises 12 exons. # Tissue distribution The gene is expressed in the lysosomes of all organs and tissues. Cystinosin has also been found in melanosomes in melanocytes. # Structure Cystinosin is a seven-transmembrane domain receptor embedded in the lysosomal membrane, and is a member of the lysosomal cystine transporter family of transport proteins. It comprises 367 amino acid residues, and has a molecular mass of 41738 Da. Cystinosin has seven N-glycosylation sites in the N-terminus region, spanning a range of 128 amino acid residues. The receptor also has two sorting motifs; a GYDQL motif in the C-terminus region, and a YFPQA motif, known as the 'PQ loop,' on the fifth inter-transmembrane α-helix moiety. # Mechanism The protein obeys Michaelis-Menton kinetics and has an associated KM of 278 ± 49 µM. # Function Cystinosin functions as a symporter which actively transports protons and cystine, the oxidized cysteine dimer, out of the lysosome. This is necessary to distribute cystine to the rest of the cell and allow the lysosome to continue to function. Cystinosin has also been discovered in melanosomes and has been linked to the control and regulation of melanin. # Clinical significance ## Cystinosis Mutations in CTNS can result in cystinosis. Cystinosis is a type of lysosomal transport disorder, a subset of lysosomal storage disorders. Variation in the encoded cystinosin protein results in an inhibition or loss in its ability to transport cysteine out of the lysosome. Cysteine molecules accumulate and form crystals within the lysosome, impairing its function. ## Mutations Cystinosis is presented in patients with a range of CTNS mutations; as of 2017, over 100 have been identified. The most common mutation is a 57,257 base pair deletion commonly referred to as the 57 kb deletion. This was formally known as the 65 kb deletion; a misnomer originating from early incorrect estimates. Other reported mutations include other deletions, missense mutations, and in-frame deletions and insertions. The type and extent of mutation determines the type and severity of cystinosis in the carrier. This is a result of the degree of transport inhibition caused by the misfolding of cystinosin. For example, mild cystinosis is typically associated with mutations that do not affect the amino acids in the transmembrane domains of cystinosin. In contrast, infantile nephropathic cystinosis, the most severe form of the disease, is most commonly associated with a total loss of activity. Gene deletion resulting in the absence of either of the sorting motifs results in the delocalization of cystinosin to the cellular plasma membrane. # Model systems Human models for cystinosin are typically derived from cystinotic renal tubular cell lines. Non-human protein homologs for cystinosin include ERS1 in Saccharomyces cerevisiae (yeast cells) and the Caenorhabditis elegans protein, C41C4.7. Murine ctns has also been used.	CTNS (gene) CTNS may also refer to the Center for Theology and the Natural Sciences. CTNS is the gene that encodes the protein cystinosin in humans. Cystinosin is a lysosomal seven-transmembrane protein that functions as an active transporter for the export of cystine molecules out of the lysosome. Mutations in CTNS are responsible for cystinosis, an autosomal recessive lysosomal storage disease.[1] # Discovery In 1995, the gene was localized to the short arm of chromosome 17.[2] An international collaborative effort finally succeeded in isolating CTNS by positional cloning in 1998.[1] # Gene CTNS is located on the p arm of human chromosome 17, at position 13.2.[1] It spans base pairs 3,636,468 and 3,661,542, and comprises 12 exons.[1][3] # Tissue distribution The gene is expressed in the lysosomes of all organs and tissues.[4] Cystinosin has also been found in melanosomes in melanocytes.[5] # Structure Cystinosin is a seven-transmembrane domain receptor embedded in the lysosomal membrane, and is a member of the lysosomal cystine transporter family of transport proteins.[6] It comprises 367 amino acid residues, and has a molecular mass of 41738 Da.[6] Cystinosin has seven N-glycosylation sites in the N-terminus region, spanning a range of 128 amino acid residues.[7] The receptor also has two sorting motifs; a GYDQL motif in the C-terminus region, and a YFPQA motif, known as the 'PQ loop,' on the fifth inter-transmembrane α-helix moiety.[8] # Mechanism The protein obeys Michaelis-Menton kinetics and has an associated KM of 278 ± 49 µM.[7][9] # Function Cystinosin functions as a symporter which actively transports protons and cystine, the oxidized cysteine dimer, out of the lysosome.[7] This is necessary to distribute cystine to the rest of the cell and allow the lysosome to continue to function. Cystinosin has also been discovered in melanosomes and has been linked to the control and regulation of melanin.[5] # Clinical significance ## Cystinosis Mutations in CTNS can result in cystinosis. Cystinosis is a type of lysosomal transport disorder, a subset of lysosomal storage disorders.[10] Variation in the encoded cystinosin protein results in an inhibition or loss in its ability to transport cysteine out of the lysosome. Cysteine molecules accumulate and form crystals within the lysosome, impairing its function.[4] ## Mutations Cystinosis is presented in patients with a range of CTNS mutations; as of 2017, over 100 have been identified.[11][12] The most common mutation is a 57,257 base pair deletion commonly referred to as the 57 kb deletion. This was formally known as the 65 kb deletion; a misnomer originating from early incorrect estimates.[13][14] Other reported mutations include other deletions, missense mutations, and in-frame deletions and insertions.[15][16] The type and extent of mutation determines the type and severity of cystinosis in the carrier.[17] This is a result of the degree of transport inhibition caused by the misfolding of cystinosin.[15] For example, mild cystinosis is typically associated with mutations that do not affect the amino acids in the transmembrane domains of cystinosin.[3] In contrast, infantile nephropathic cystinosis, the most severe form of the disease, is most commonly associated with a total loss of activity.[15] Gene deletion resulting in the absence of either of the sorting motifs results in the delocalization of cystinosin to the cellular plasma membrane.[18][7] # Model systems Human models for cystinosin are typically derived from cystinotic renal tubular cell lines.[19][20] Non-human protein homologs for cystinosin include ERS1 in Saccharomyces cerevisiae (yeast cells) and the Caenorhabditis elegans protein, C41C4.7.[21] Murine ctns has also been used.[22]	https://www.wikidoc.org/index.php/CTNS_(gene)
d1f1f3b8a7d30ddc45c7622007ba870d3b21666d	wikidoc	CT template	CT template To go to the main page, click here. # Introduction to the CT or MRI Page - The page name should be "(Disease name) CT or MRI", with only the first letter of the title and the letters "CT" or "MRI" capitalized. - Goal: To provide a description and examples the CT findings that might be seen with the disease you are describing. - As with all microchapter pages linking to the main page, at the top of the edit box put {{CMG}}, your name template, and the microchapter navigation template you created at the beginning. - Remember to create links within Wikidoc by placing ] around key words which you want to link to other pages. Make sure you makes your links as specific as possible. For example if a sentence contained the phrase anterior spinal artery syndrome, the link should be to anterior spinal artery syndrome not anterior or artery or syndrome. For more information on how to create links click here. - Remember to follow the same format and capitalization of letters as outlined in the template below. - You should include the name of the disease in the first sentence of every subsection. # Overview - The overview section should include the disease name in the first sentence. - The goal is to summarize the CT or MRI findings page in several sentences. This section can be the same as the CT or MRI segment on the overview page. - To see an example of an overview section on a CT page, click here. ## Template - First Sentences: CT scan is diagnostic of . - Examples: # Preferred Template Statements IF there are no CT findings associated with the disease: - There are no CT scan findings associated with . IF a CT scan is useful for diagnosis: - CT scan may be helpful in the diagnosis of . Findings on CT scan suggestive of/diagnostic of include , , and . IF a CT scan is not helpful for diagnosis, but may be helpful in identifying complications of the disease: - There are no CT scan findings associated with . However, a CT scan may be helpful in the diagnosis of complications of , which include , , and . # Key CT or MRI Findings in (Disease Name) - Describe in detail the CT or MRI findings that may be seen in the disease you are describing, as well as in sub-classifications of the disease, and associated conditions. - Describe how the CT or MRI findings relate to the underlying pathophysiology of the disease. # CT or MRI Examples of (Disease Name) - Here you should provide visual examples of CT or MRI findings for the disease you are describing. Good copyleft source to use for images is RadsWiki , National Library of Medicine (/), Wikipedia (), or Radiopedia (/). - Good copyleft source to use for images is RadsWiki , National Library of Medicine (/), Wikipedia (), or Radiopedia (/). - For help on how to insert images, click here.	CT template To go to the main page, click here. Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2] # Introduction to the CT or MRI Page - The page name should be "(Disease name) CT or MRI", with only the first letter of the title and the letters "CT" or "MRI" capitalized. - Goal: To provide a description and examples the CT findings that might be seen with the disease you are describing. - As with all microchapter pages linking to the main page, at the top of the edit box put {{CMG}}, your name template, and the microchapter navigation template you created at the beginning. - Remember to create links within Wikidoc by placing [[square brackets]] around key words which you want to link to other pages. Make sure you makes your links as specific as possible. For example if a sentence contained the phrase anterior spinal artery syndrome, the link should be to anterior spinal artery syndrome not anterior or artery or syndrome. For more information on how to create links click here. - Remember to follow the same format and capitalization of letters as outlined in the template below. - You should include the name of the disease in the first sentence of every subsection. # Overview - The overview section should include the disease name in the first sentence. - The goal is to summarize the CT or MRI findings page in several sentences. This section can be the same as the CT or MRI segment on the overview page. - To see an example of an overview section on a CT page, click here. ## Template - First Sentences: [Location] CT scan is diagnostic of [disease name]. - Examples: # Preferred Template Statements IF there are no CT findings associated with the disease: - There are no CT scan findings associated with [disease name]. IF a CT scan is useful for diagnosis: - [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]. IF a CT scan is not helpful for diagnosis, but may be helpful in identifying complications of the disease: - 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]. # Key CT or MRI Findings in (Disease Name) - Describe in detail the CT or MRI findings that may be seen in the disease you are describing, as well as in sub-classifications of the disease, and associated conditions. - Describe how the CT or MRI findings relate to the underlying pathophysiology of the disease. # CT or MRI Examples of (Disease Name) - Here you should provide visual examples of CT or MRI findings for the disease you are describing. Good copyleft source to use for images is RadsWiki http://www.radswiki.net/main/index.php?title=Main_Page, National Library of Medicine (http://www.nlm.nih.gov/), Wikipedia (http://wikipedia.org), or Radiopedia (http://radiopaedia.org/). - Good copyleft source to use for images is RadsWiki http://www.radswiki.net/main/index.php?title=Main_Page, National Library of Medicine (http://www.nlm.nih.gov/), Wikipedia (http://wikipedia.org), or Radiopedia (http://radiopaedia.org/). - For help on how to insert images, click here.	https://www.wikidoc.org/index.php/CT_template
c56f56c4fcc87e517fd0ec597a951cc09ca9f2ea	wikidoc	Chest X-ray	Chest X-ray # Overview A chest X-ray, commonly abbreviated CXR, is a projection radiograph (X-ray), taken by a radiographer, of the thorax which is used to diagnose problems with that area. # Problems identified through chest x-rays Examples of such problems include but are not limited to: - Pneumothorax, sometimes tension pneumothorax (though this is usually diagnosed clinically because of its acute nature) - Rib fracture - Air space disease/consolidation (e.g. pneumonia) - Interstitial lung disease (e.g. idiopathic pulmonary fibrosis (IPF), lung cancer, active tuberculosis) - Cardiac silhouette enlargement - congestive heart failure, pericardial effusion, hypertrophic cardiomyopathies - Pleural effusion - Peritonitis - Hiatal hernia - Emphysema - Pulmonary embolism (rarely) - usually CXR is normal - Dissecting aortic aneurysm (due to trauma, advanced/untreated syphilis, connective tissue disorders) Chest X-Rays are among the most common films taken, being diagnostic of so many important problems. # Features that are typically examined on a chest X-ray Every doctor will have a different approach to examining chest X-rays. A commonly used mnemonic for what to look for on a chest X-ray is: It May Prove Quite Right (but) Stop And Be Certain How Lungs Appear: - I = Identification (name, age, sex, indication for X-ray) - M = Markers (differentiate left from right - diagnose dextrocardia) - P = Position - the spinous process of T4 should be between the heads of the clavicle (if it isn't the body is rotated) - Q = Quality - is the film penetrated properly. In a properly penetrated film the vertebral interspaces should be visible behind the central (cardiac) shadow - R = Respiration - chest X-rays are typically done with full inspiration - (but) - S = Soft tissue - look for subcutaneous emphysema (suggestive of trauma), soft tissue swelling - A = Abdomen - look for free abdominal air (suggests penetrating trauma, peritonitis, or recent surgery) - B = Bone - look for fractures (these tend to be at the lateral aspects because of the mechanics - bending moment largest at lateral aspect) - C = Central shadow (cardiac silhouette) - greater than 50% of lateral distance in frontal view at the diaphragm suggests cardiac enlargement (usually secondary to heart failure) or a pericardial effusion). A widened mediastinum may suggest aortic dissection. - H = Hila (of the lungs) - can be affected in lung disease, malignant processes and infection (hilar lymphadenopathy). - L = Lungs - for consolidation, interstitial lung disease (reticular, nodular or reticulonodular), honeycombing, miliary pattern, granulomas, lung masses - A = Absent structures/Apices of the lung (for pneumothorax) Another approach is to examine first any major abnormality, and then "review areas": - the apices, - the hila, - behind the heart (it must be remembered that lung can be seen through the heart), - the cardiophrenic angles, - the costophrenic angles, - beneath the diaphragm, and then - bone and soft tissues. A third approach is: - Inspection of chest Centralized - Check whether the Xray is centralized. In a well centralized film the clavicle is equidistant from the spines of the vertebral body. It is important when we are commenting on the comparative radiolucency of the lung field, cardiomegaly and mediastenal shift. Compare the lung field on upper, middle, and lower zone to check for radiolucency on both side of lungs at equal levels. Check the apical area (just behind the clavicle) for the changes due to tuberculosis. Check for any cervical rib in cases of bony deformities Check for cardiophrenic and costophrenic angles. These are sharp and curved in healthy individuals. The right diaphragm is .5 - 1.5 cm higher than the left diaphragm. Check the hila for any hilar lymphadenopathy. The left hilum is slightly higher than the right Trace trachea up to the carina to check for any deviation. - Centralized - Check whether the Xray is centralized. In a well centralized film the clavicle is equidistant from the spines of the vertebral body. It is important when we are commenting on the comparative radiolucency of the lung field, cardiomegaly and mediastenal shift. - Compare the lung field on upper, middle, and lower zone to check for radiolucency on both side of lungs at equal levels. - Check the apical area (just behind the clavicle) for the changes due to tuberculosis. - Check for any cervical rib in cases of bony deformities - Check for cardiophrenic and costophrenic angles. These are sharp and curved in healthy individuals. The right diaphragm is .5 - 1.5 cm higher than the left diaphragm. - Check the hila for any hilar lymphadenopathy. The left hilum is slightly higher than the right - Trace trachea up to the carina to check for any deviation. - Inspection of the cardiac silhouette Check the cardiac borders. Left cardiac border is formed by aorta, pulmonary conus, left atrium, and right atrium from top to bottom. The right border is formed by superior vena cava and right atrium Measure the cardio-thoracic ratio to rule out any cardiomegaly. To measure the cardiothoracic ratio draw a vertical line through the spine of the vertebrae. Draw lines perpendicular from this line to the maximum width of the left (say for e.g. a) and right heart borders (say for e.g. b). The summation of a and b should be less than half of the maximum transverse diameter of the chest (say for e.g. c). Thus a+b = or < C/2 - Check the cardiac borders. Left cardiac border is formed by aorta, pulmonary conus, left atrium, and right atrium from top to bottom. The right border is formed by superior vena cava and right atrium - Measure the cardio-thoracic ratio to rule out any cardiomegaly. To measure the cardiothoracic ratio draw a vertical line through the spine of the vertebrae. Draw lines perpendicular from this line to the maximum width of the left (say for e.g. a) and right heart borders (say for e.g. b). The summation of a and b should be less than half of the maximum transverse diameter of the chest (say for e.g. c). Thus a+b = or < C/2 - Inspection of bones - Check ribs for crowding, spreading and bony lesions - Check clavicle, scapula, and shoulder joints - Inspection of soft tissue Check chest muscles, subcutaneous tissue, and breast in females - Check chest muscles, subcutaneous tissue, and breast in females # Views ## Typical views - Frontal (view) PA (posterior-anterior) AP (anterior-posterior) - these are typically done in the ICU - PA (posterior-anterior) - AP (anterior-posterior) - these are typically done in the ICU - Lateral (view) The most common view is the PA (posterior-anterior) and is frequently done with a left lateral view (so one can identify the location of abnormalities in 3-D space). PA views are generally preferred to AP views (which are often done with mobile/portable X-ray equipment), but much less convenient in the ICU setting or when a patient cannot otherwise leave their bed. PA views are preferred because the central shadow is better defined, the magnification of the heart is reduced, and less of the lungs obscured by the heart/pericardial sac. ## Additional views - Decubitus - useful for differentiating pleural effusions from consolidation (e.g. pneumonia). In effusions, the fluid layers out (by comparison to an up-right view, when it often accumulates in the costophrenic angles). - Lordotic view - used to visualize the apex of the lung, to pick-up abnormalities such as a Pancoast tumour. - Expiratory view - helpful for the diagnosis of pneumothorax - Obliques # Chest X Ray findings in some common lung diseases ## Tuberculosis chest x ray # Abnormalities ## Nodule A nodule is a discrete opacity in the lung which may be caused by: - Neoplasm: benign or malignant - Granuloma: tuberculosis - Infection: round pneumonia - Vascular: infarction, varix, Wegener's granulomatosis, rheumatoid arthritis There are a number of features that are helpful in suggesting the diagnosis: - rate of growth Doubling time of less than one month: sarcoma/infection/infarction/vascular Doubling time of six to 18 months: benign tumour/malignant granuloma Doubling time of more than 24 months: benign nodule - Doubling time of less than one month: sarcoma/infection/infarction/vascular - Doubling time of six to 18 months: benign tumour/malignant granuloma - Doubling time of more than 24 months: benign nodule - calcification - margin smooth lobulated presence of a corona radiata - smooth - lobulated - presence of a corona radiata - shape - site If the nodules are multiple, the differential is then smaller: - infection: tuberculosis, fungal infection, septic emboli - neoplasm: e.g., metastases, lymphoma, harmatoma - sarcoidosis - alveolitis - auto-immune disease: e.g., Wegener's granulomatosis, rheumatoid arthritis - inhalation (e.g., pneumoconiosis) ## Cavities A cavity is a walled hollow structure within the lungs. Diagnosis is aided by noting: - wall thickness - wall outline - changes in the surrounding lung The causes include: - cancer (usually malignant) - infarction (usually from a pulmonary embolus) - infection: e.g., Staphylococcus aureus, tuberculosis, Gram negative bacteria (especially Klebsiella pneumoniae), and anaerobic bacteria. ## Pleural abnormalities Fluid in space between the lung and the chest wall is termed a pleural effusion. There needs to be at least 75ml of pleural fluid in order to blunt the costophrenic angle on the lateral chest X-ray, and 200ml on the posteroanterior chest X-ray. On a lateral decubitus, amounts as small as 5ml of fluid are possible. Pleural effusions typically have a meniscus visible on an erect chest X-ray, but loculated effusions (as occur with an empyema) may have a lenticular shape (the fluid making an obtuse angle with the chest wall). Pleural thickening may cause blunting of the costophrenic angle, but is distinguished from pleural fluid by the fact that is occurs as a linear shadow ascending vertically and clinging to the ribs. ## Diffuse shadowing The differential for diffuse shadowing is very broad and can defeat even the most experienced radiologist. It is seldom possible to reach a diagnosis on the basis of the chest X-ray alone: high-resolution CT of the chest is usually required and sometimes a lung biopsy. The following features should be noted: - type of shadowing (lines, dots or rings) reticular (crisscrossing lines) nodular (lots of small dots) rings or cysts ground glass consolidation (diffuse opacity with air bronchograms) - reticular (crisscrossing lines) - nodular (lots of small dots) - rings or cysts - ground glass - consolidation (diffuse opacity with air bronchograms) - location (where is the lesion worst?) upper zone (e.g., sarcoid, tuberculosis, silicosis/pneumoconiosis, ankylosing spondylitis, Langerhans cell histiocytosis) lower zone (e.g., cryptogenic fibrosing alveolitis, connective tissue disease, asbestosis, drug reactions) central (e.g., pulmonary oedema, alveolar proteinosis, lymphoma, Kaposi's sarcoma, PCP) peripheral (e.g., cryptogenic fibrosing alveolitis, connective tissue disease,chronic eosinophilic pneumonia, bronchiolitis obliterans organizing pneumonia) - upper zone (e.g., sarcoid, tuberculosis, silicosis/pneumoconiosis, ankylosing spondylitis, Langerhans cell histiocytosis) - lower zone (e.g., cryptogenic fibrosing alveolitis, connective tissue disease, asbestosis, drug reactions) - central (e.g., pulmonary oedema, alveolar proteinosis, lymphoma, Kaposi's sarcoma, PCP) - peripheral (e.g., cryptogenic fibrosing alveolitis, connective tissue disease,chronic eosinophilic pneumonia, bronchiolitis obliterans organizing pneumonia) - lung volume increased (e.g., Langerhans cell histiocytosis, lymphangioleiomyomatosis, cystic fibrosis, allergic bronchopulmonary aspergillosis) decreased (e.g., fibrotic lung disease, chronic sarcoidosis, chronic extrinsic allergic alveolitis) - increased (e.g., Langerhans cell histiocytosis, lymphangioleiomyomatosis, cystic fibrosis, allergic bronchopulmonary aspergillosis) - decreased (e.g., fibrotic lung disease, chronic sarcoidosis, chronic extrinsic allergic alveolitis) Pleural effusions may occur with cancer, sarcoid, connective tissue diseases and lymphangioleiomyomatosis. The presence of a pleural effusion argues against pneumocystis pneumonia. - cryptogenic fibrosing alveolitis - connective tissue disease - sarcoidosis - radiation fibrosis - asbestosis - lymphangitis carcinomatosis - sarcoidosis - silicosis/pneumoconiosis - extrinsic allergic alveolitis - Langerhans cell histiocytosis - lymphangitis carcinomatosis - miliary tuberculosis - metastases - cryptogenic fibrosing alveolitis (late stage "honeycomb lung") - cystic bronchiectasis - Langerhans cell histocytosis - lymphangioleiomyomatosis - Extrinsic allergic alveolitis - Diffuse interstitial pneumonitis - Alveolar proteinosis - Alveolar haemorrhage - Alveolar cell carcinoma - vasculitis - chronic eosinophilic pneumonia # Limitations It must be remembered that while the chest X-ray is a cheap and safe method of investigating diseases of the chest, there are a number of serious chest conditions that may be associated with a normal chest X-ray and other means of assessment may be necessary to make the diagnosis: - Asthma - Chronic obstructive pulmonary disease - Pneumocystis jiroveci pneumonia (PCP) - Pulmonary embolism - Smoke inhalation - Foreign body inhalation ## Signs - The silhouette sign is especially helpful in localizing lung lesions. (e.g., loss of right heart border in right middle lobe pneumonia), - The air bronchogram sign, where branching radiolucent columns of air corresponding to bronchi is seen, usually indicates air-space (alveolar) disease, as from blood, pus, mucus, cells, protein surrounding the air bronchograms. This is seen in Respiratory distress syndrome - The "bean" sign first described by Professor Keval Pandya is the appearance of a sharply circumscribed bean shaped nodule on chest X-ray which has a high sensitivity and specificity (92% and 88%) for the presence of miliary TB.	Chest X-ray Template:Interventions infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A chest X-ray, commonly abbreviated CXR, is a projection radiograph (X-ray), taken by a radiographer, of the thorax which is used to diagnose problems with that area. # Problems identified through chest x-rays Examples of such problems include but are not limited to: - Pneumothorax, sometimes tension pneumothorax (though this is usually diagnosed clinically because of its acute nature) - Rib fracture - Air space disease/consolidation (e.g. pneumonia) - Interstitial lung disease (e.g. idiopathic pulmonary fibrosis (IPF), lung cancer, active tuberculosis) - Cardiac silhouette enlargement - congestive heart failure, pericardial effusion, hypertrophic cardiomyopathies - Pleural effusion - Peritonitis - Hiatal hernia - Emphysema - Pulmonary embolism (rarely) - usually CXR is normal - Dissecting aortic aneurysm (due to trauma, advanced/untreated syphilis, connective tissue disorders) Chest X-Rays are among the most common films taken, being diagnostic of so many important problems. # Features that are typically examined on a chest X-ray Every doctor will have a different approach to examining chest X-rays. A commonly used mnemonic for what to look for on a chest X-ray is: It May Prove Quite Right (but) Stop And Be Certain How Lungs Appear: - I = Identification (name, age, sex, indication for X-ray) - M = Markers (differentiate left from right - diagnose dextrocardia) - P = Position - the spinous process of T4 should be between the heads of the clavicle (if it isn't the body is rotated) - Q = Quality - is the film penetrated properly. In a properly penetrated film the vertebral interspaces should be visible behind the central (cardiac) shadow - R = Respiration - chest X-rays are typically done with full inspiration - (but) - S = Soft tissue - look for subcutaneous emphysema (suggestive of trauma), soft tissue swelling - A = Abdomen - look for free abdominal air (suggests penetrating trauma, peritonitis, or recent surgery) - B = Bone - look for fractures (these tend to be at the lateral aspects because of the mechanics - bending moment largest at lateral aspect) - C = Central shadow (cardiac silhouette) - greater than 50% of lateral distance in frontal view at the diaphragm suggests cardiac enlargement (usually secondary to heart failure) or a pericardial effusion). A widened mediastinum may suggest aortic dissection. - H = Hila (of the lungs) - can be affected in lung disease, malignant processes and infection (hilar lymphadenopathy). - L = Lungs - for consolidation, interstitial lung disease (reticular, nodular or reticulonodular), honeycombing, miliary pattern, granulomas, lung masses - A = Absent structures/Apices of the lung (for pneumothorax) Another approach is to examine first any major abnormality, and then "review areas": - the apices, - the hila, - behind the heart (it must be remembered that lung can be seen through the heart), - the cardiophrenic angles, - the costophrenic angles, - beneath the diaphragm, and then - bone and soft tissues. A third approach is: - Inspection of chest Centralized - Check whether the Xray is centralized. In a well centralized film the clavicle is equidistant from the spines of the vertebral body. It is important when we are commenting on the comparative radiolucency of the lung field, cardiomegaly and mediastenal shift. Compare the lung field on upper, middle, and lower zone to check for radiolucency on both side of lungs at equal levels. Check the apical area (just behind the clavicle) for the changes due to tuberculosis. Check for any cervical rib in cases of bony deformities Check for cardiophrenic and costophrenic angles. These are sharp and curved in healthy individuals. The right diaphragm is .5 - 1.5 cm higher than the left diaphragm. Check the hila for any hilar lymphadenopathy. The left hilum is slightly higher than the right Trace trachea up to the carina to check for any deviation. - Centralized - Check whether the Xray is centralized. In a well centralized film the clavicle is equidistant from the spines of the vertebral body. It is important when we are commenting on the comparative radiolucency of the lung field, cardiomegaly and mediastenal shift. - Compare the lung field on upper, middle, and lower zone to check for radiolucency on both side of lungs at equal levels. - Check the apical area (just behind the clavicle) for the changes due to tuberculosis. - Check for any cervical rib in cases of bony deformities - Check for cardiophrenic and costophrenic angles. These are sharp and curved in healthy individuals. The right diaphragm is .5 - 1.5 cm higher than the left diaphragm. - Check the hila for any hilar lymphadenopathy. The left hilum is slightly higher than the right - Trace trachea up to the carina to check for any deviation. - Inspection of the cardiac silhouette Check the cardiac borders. Left cardiac border is formed by aorta, pulmonary conus, left atrium, and right atrium from top to bottom. The right border is formed by superior vena cava and right atrium Measure the cardio-thoracic ratio to rule out any cardiomegaly. To measure the cardiothoracic ratio draw a vertical line through the spine of the vertebrae. Draw lines perpendicular from this line to the maximum width of the left (say for e.g. a) and right heart borders (say for e.g. b). The summation of a and b should be less than half of the maximum transverse diameter of the chest (say for e.g. c). Thus a+b = or < C/2 - Check the cardiac borders. Left cardiac border is formed by aorta, pulmonary conus, left atrium, and right atrium from top to bottom. The right border is formed by superior vena cava and right atrium - Measure the cardio-thoracic ratio to rule out any cardiomegaly. To measure the cardiothoracic ratio draw a vertical line through the spine of the vertebrae. Draw lines perpendicular from this line to the maximum width of the left (say for e.g. a) and right heart borders (say for e.g. b). The summation of a and b should be less than half of the maximum transverse diameter of the chest (say for e.g. c). Thus a+b = or < C/2 - Inspection of bones - Check ribs for crowding, spreading and bony lesions - Check clavicle, scapula, and shoulder joints - Inspection of soft tissue Check chest muscles, subcutaneous tissue, and breast in females - Check chest muscles, subcutaneous tissue, and breast in females # Views ## Typical views - Frontal (view) PA (posterior-anterior) AP (anterior-posterior) - these are typically done in the ICU - PA (posterior-anterior) - AP (anterior-posterior) - these are typically done in the ICU - Lateral (view) The most common view is the PA (posterior-anterior) and is frequently done with a left lateral view (so one can identify the location of abnormalities in 3-D space). PA views are generally preferred to AP views (which are often done with mobile/portable X-ray equipment), but much less convenient in the ICU setting or when a patient cannot otherwise leave their bed. PA views are preferred because the central shadow is better defined, the magnification of the heart is reduced, and less of the lungs obscured by the heart/pericardial sac. ## Additional views - Decubitus - useful for differentiating pleural effusions from consolidation (e.g. pneumonia). In effusions, the fluid layers out (by comparison to an up-right view, when it often accumulates in the costophrenic angles). - Lordotic view - used to visualize the apex of the lung, to pick-up abnormalities such as a Pancoast tumour. - Expiratory view - helpful for the diagnosis of pneumothorax - Obliques # Chest X Ray findings in some common lung diseases ## Tuberculosis chest x ray # Abnormalities ## Nodule A nodule is a discrete opacity in the lung which may be caused by: - Neoplasm: benign or malignant - Granuloma: tuberculosis - Infection: round pneumonia - Vascular: infarction, varix, Wegener's granulomatosis, rheumatoid arthritis There are a number of features that are helpful in suggesting the diagnosis: - rate of growth Doubling time of less than one month: sarcoma/infection/infarction/vascular Doubling time of six to 18 months: benign tumour/malignant granuloma Doubling time of more than 24 months: benign nodule - Doubling time of less than one month: sarcoma/infection/infarction/vascular - Doubling time of six to 18 months: benign tumour/malignant granuloma - Doubling time of more than 24 months: benign nodule - calcification - margin smooth lobulated presence of a corona radiata - smooth - lobulated - presence of a corona radiata - shape - site If the nodules are multiple, the differential is then smaller: - infection: tuberculosis, fungal infection, septic emboli - neoplasm: e.g., metastases, lymphoma, harmatoma - sarcoidosis - alveolitis - auto-immune disease: e.g., Wegener's granulomatosis, rheumatoid arthritis - inhalation (e.g., pneumoconiosis) ## Cavities A cavity is a walled hollow structure within the lungs. Diagnosis is aided by noting: - wall thickness - wall outline - changes in the surrounding lung The causes include: - cancer (usually malignant) - infarction (usually from a pulmonary embolus) - infection: e.g., Staphylococcus aureus, tuberculosis, Gram negative bacteria (especially Klebsiella pneumoniae), and anaerobic bacteria. ## Pleural abnormalities Fluid in space between the lung and the chest wall is termed a pleural effusion. There needs to be at least 75ml of pleural fluid in order to blunt the costophrenic angle on the lateral chest X-ray, and 200ml on the posteroanterior chest X-ray. On a lateral decubitus, amounts as small as 5ml of fluid are possible. Pleural effusions typically have a meniscus visible on an erect chest X-ray, but loculated effusions (as occur with an empyema) may have a lenticular shape (the fluid making an obtuse angle with the chest wall). Pleural thickening may cause blunting of the costophrenic angle, but is distinguished from pleural fluid by the fact that is occurs as a linear shadow ascending vertically and clinging to the ribs. ## Diffuse shadowing The differential for diffuse shadowing is very broad and can defeat even the most experienced radiologist. It is seldom possible to reach a diagnosis on the basis of the chest X-ray alone: high-resolution CT of the chest is usually required and sometimes a lung biopsy. The following features should be noted: - type of shadowing (lines, dots or rings) reticular (crisscrossing lines) nodular (lots of small dots) rings or cysts ground glass consolidation (diffuse opacity with air bronchograms) - reticular (crisscrossing lines) - nodular (lots of small dots) - rings or cysts - ground glass - consolidation (diffuse opacity with air bronchograms) - location (where is the lesion worst?) upper zone (e.g., sarcoid, tuberculosis, silicosis/pneumoconiosis, ankylosing spondylitis, Langerhans cell histiocytosis) lower zone (e.g., cryptogenic fibrosing alveolitis, connective tissue disease, asbestosis, drug reactions) central (e.g., pulmonary oedema, alveolar proteinosis, lymphoma, Kaposi's sarcoma, PCP) peripheral (e.g., cryptogenic fibrosing alveolitis, connective tissue disease,chronic eosinophilic pneumonia, bronchiolitis obliterans organizing pneumonia) - upper zone (e.g., sarcoid, tuberculosis, silicosis/pneumoconiosis, ankylosing spondylitis, Langerhans cell histiocytosis) - lower zone (e.g., cryptogenic fibrosing alveolitis, connective tissue disease, asbestosis, drug reactions) - central (e.g., pulmonary oedema, alveolar proteinosis, lymphoma, Kaposi's sarcoma, PCP) - peripheral (e.g., cryptogenic fibrosing alveolitis, connective tissue disease,chronic eosinophilic pneumonia, bronchiolitis obliterans organizing pneumonia) - lung volume increased (e.g., Langerhans cell histiocytosis, lymphangioleiomyomatosis, cystic fibrosis, allergic bronchopulmonary aspergillosis) decreased (e.g., fibrotic lung disease, chronic sarcoidosis, chronic extrinsic allergic alveolitis) - increased (e.g., Langerhans cell histiocytosis, lymphangioleiomyomatosis, cystic fibrosis, allergic bronchopulmonary aspergillosis) - decreased (e.g., fibrotic lung disease, chronic sarcoidosis, chronic extrinsic allergic alveolitis) Pleural effusions may occur with cancer, sarcoid, connective tissue diseases and lymphangioleiomyomatosis. The presence of a pleural effusion argues against pneumocystis pneumonia. - cryptogenic fibrosing alveolitis - connective tissue disease - sarcoidosis - radiation fibrosis - asbestosis - lymphangitis carcinomatosis - sarcoidosis - silicosis/pneumoconiosis - extrinsic allergic alveolitis - Langerhans cell histiocytosis - lymphangitis carcinomatosis - miliary tuberculosis - metastases - cryptogenic fibrosing alveolitis (late stage "honeycomb lung") - cystic bronchiectasis - Langerhans cell histocytosis - lymphangioleiomyomatosis - Extrinsic allergic alveolitis - Diffuse interstitial pneumonitis - Alveolar proteinosis - Alveolar haemorrhage - Alveolar cell carcinoma - vasculitis - chronic eosinophilic pneumonia # Limitations It must be remembered that while the chest X-ray is a cheap and safe method of investigating diseases of the chest, there are a number of serious chest conditions that may be associated with a normal chest X-ray and other means of assessment may be necessary to make the diagnosis: - Asthma - Chronic obstructive pulmonary disease - Pneumocystis jiroveci pneumonia (PCP) - Pulmonary embolism - Smoke inhalation - Foreign body inhalation ## Signs - The silhouette sign is especially helpful in localizing lung lesions. (e.g., loss of right heart border in right middle lobe pneumonia),[1] - The air bronchogram sign, where branching radiolucent columns of air corresponding to bronchi is seen, usually indicates air-space (alveolar) disease, as from blood, pus, mucus, cells, protein surrounding the air bronchograms. This is seen in Respiratory distress syndrome[1] - The "bean" sign first described by Professor Keval Pandya is the appearance of a sharply circumscribed bean shaped nodule on chest X-ray which has a high sensitivity and specificity (92% and 88%) for the presence of miliary TB.	https://www.wikidoc.org/index.php/CXR
28c50518cb21e56a23004bd55f99faf6e1f906fe	wikidoc	Cabazitaxel	Cabazitaxel # 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 Cabazitaxel is a antineoplasic agent that is FDA approved for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Cabazitaxel® is a microtubule inhibitor indicated in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen. ### Dosage - The individual dosage of Cabazitaxel is based on calculation of the Body Surface Area (BSA) and is 25 mg/m2 administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout Cabazitaxel treatment. - Premedication is recommended prior to treatment. - Cabazitaxel should be administered under the supervision of a qualified physician experienced in the use of antineoplastic medicinal products. Appropriate management of complications is possible only when the adequate diagnostic and treatment facilities are readily available. - Cabazitaxel Injection single-use vial requires two dilutions prior to administration. - Do not use PVC infusion containers and polyurethane infusions sets for preparation and administration of Cabazitaxel infusion solution. - Both the Cabazitaxel Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. - The Cabazitaxel dose should be reduced if patients experience the following adverse reactions. - Discontinue Cabazitaxel treatment if a patient continues to experience any of these reactions at 20 mg/m2. - Concomitant drugs that are strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the coadministration of Cabazitaxel with these drugs. If patients require co-administration of a strong CYP3A inhibitor, consider a 25% Cabazitaxel dose reduction ### DOSAGE FORMS AND STRENGTHS - Cabazitaxel (cabazitaxel) Injection 60 mg/1.5 mL is supplied as a kit consisting of the following: - Cabazitaxel Injection 60 mg/1.5 mL: contains 60 mg cabazitaxel in 1.5 mL polysorbate 80, - Diluent for Cabazitaxel Injection 60 mg/1.5 mL: contains approximately 5.7 mL of 13% (w/w) ethanol in water for injection. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cabazitaxel in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cabazitaxel in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Cabazitaxel in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cabazitaxel in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cabazitaxel in pediatric patients. # Contraindications - Cabazitaxel should not be used in patients with neutrophil counts of ≤ 1,500/mm3. - Cabazitaxel is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80. # Warnings - Five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient's death was attributed to neutropenia without a documented infection. - G-CSF may be administered to reduce the risks of neutropenia complications associated with Cabazitaxel use. Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age > 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients considered to be at increased risk for neutropenia complications. - Monitoring of complete blood counts is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed. - Cabazitaxel should not be administered to patients with neutrophils ≤ 1,500/mm3. - If a patient experiences febrile neutropenia or prolonged neutropenia (greater than one week) despite appropriate medication (e.g., G-CSF), the dose of Cabazitaxel should be reduced. Patients can restart treatment with Cabazitaxel only when neutrophil counts recover to a level > 1,500/mm3. - All patients should be premedicated prior to the initiation of the infusion of Cabazitaxel. Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of Cabazitaxel, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of the Cabazitaxel infusion and appropriate therapy. Patients with a history of severe hypersensitivity reactions should not be re-challenged with Cabazitaxel. - Nausea, vomiting and severe diarrhea, at times, may occur. Death related to diarrhea and electrolyte imbalance occurred in the randomized clinical trial. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Patients should be treated with rehydration, anti-diarrheal or anti-emetic medications as needed. Treatment delay or dosage reduction may be necessary if patients experience Grade ≥ 3 diarrhea. - Gastrointestinal (GI) hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including fatal outcome, have been reported in patients treated with Cabazitaxel. Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, adhesions, ulceration and GI bleeding. - Abdominal pain and tenderness, fever, persistent constipation, diarrhea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. Cabazitaxel treatment delay or discontinuation may be necessary. - Renal failure, including four cases with fatal outcome, was reported in the randomized clinical trial. Most cases occurred in association with sepsis, dehydration, or obstructive uropathy. Some deaths due to renal failure did not have a clear etiology. Appropriate measures should be taken to identify causes of renal failure and treat aggressively. - In the randomized clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%) ≥ 65 years of age died of causes other than disease progression within 30 days of the last cabazitaxel dose. Patients ≥ 65 years of age are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia. - No dedicated hepatic impairment trial for Cabazitaxel has been conducted. Patients with impaired hepatic function (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN) were excluded from the randomized clinical trial. - Cabazitaxel is extensively metabolized in the liver, and hepatic impairment is likely to increase cabazitaxel concentrations. - Hepatic impairment increases the risk of severe and life-threatening complications in patients receiving other drugs belonging to the same class as Cabazitaxel. Cabazitaxel should not be given to patients with hepatic impairment (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN). - Pregnancy category D. - Cabazitaxel can cause fetal harm when administered to a pregnant woman. In non-clinical studies in rats and rabbits, cabazitaxel was embryotoxic, fetotoxic, and abortifacient at exposures significantly lower than those expected at the recommended human dose level. - There are no adequate and well-controlled studies in pregnant women using Cabazitaxel. 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. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with Cabazitaxel # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed in greater detail in another section of the label: - Neutropenia - Hypersensitivity Reactions - Gastrointestinal Disorders - Renal Failure - 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 safety of Cabazitaxel in combination with prednisone was evaluated in 371 patients with hormone-refractory metastatic prostate cancer treated in a single randomized trial, compared to mitoxantrone plus prednisone. - Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) Cabazitaxel-treated patients and 3 (< 1%) mitoxantrone-treated patients. The most common fatal adverse reactions in Cabazitaxel-treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of Cabazitaxel. Other fatal adverse reactions in Cabazitaxel-treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea. - The most common (≥ 10%) grade 1–4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysguesia, cough, arthralgia, and alopecia. - The most common (≥ 5%) grade 3–4 adverse reactions in patients who received Cabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. - Treatment discontinuations due to adverse drug reactions occurred in 18% of patients who received Cabazitaxel and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the Cabazitaxel group were neutropenia and renal failure. Dose reductions were reported in 12% of Cabazitaxel-treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of Cabazitaxel-treated patients and 15% of mitoxantrone-treated patients. - Five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient's death was attributed to neutropenia without a documented infection. Twenty-two (6%) patients discontinued Cabazitaxel treatment due to neutropenia, febrile neutropenia, infection, or sepsis. The most common adverse reaction leading to treatment discontinuation in the Cabazitaxel group was neutropenia (2%). - Adverse events of hematuria, including those requiring medical intervention, were more common in Cabazitaxel-treated patients. The incidence of grade ≥ 2 hematuria was 6% in Cabazitaxel-treated patients and 2% in mitoxantrone-treated patients. Other factors associated with hematuria were well-balanced between arms and do not account for the increased rate of hematuria on the Cabazitaxel arm. - The incidences of grade 3–4 increased AST, increased ALT, and increased bilirubin were each ≤ 1%. - The following grade 1–4 adverse reactions were reported at rates ≥ 5% higher in patients 65 years of age or greater compared to younger patients: fatigue (40% vs. 30%), neutropenia (97% vs. 89%), asthenia (24% vs. 15%), pyrexia (15% vs. 8%), dizziness (10% vs. 5%), urinary tract infection (10% vs. 3%) and dehydration (7% vs. 2%), respectively. - The incidence of the following grade 3–4 adverse reactions were higher in patients ≥ 65 years of age compared to younger patients; neutropenia (87% vs. 74%), and febrile neutropenia (8% vs. 6%) ## Postmarketing Experience - The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made. - Gastrointestinal: Gastritis, intestinal obstruction. # Drug Interactions - No formal clinical drug-drug interaction trials have been conducted with Cabazitaxel. - Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel. - CYP3A4 Inhibitors: Cabazitaxel is primarily metabolized through CYP3A. Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the co-administration of Cabazitaxel with strong CYP3A inhibitors. If patients require co-administration of a strong CYP3A inhibitor, consider a 25% Cabazitaxel dose reduction # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Cabazitaxel can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Cabazitaxel in pregnant women. - Non-clinical studies in rats and rabbits have shown that cabazitaxel is embryotoxic, fetotoxic, and abortifacient. Cabazitaxel was shown to cross the placenta barrier within 24 hours of a single intravenous administration of a 0.08 mg/kg dose (approximately 0.02 times the maximum recommended human dose-MRHD) to pregnant rats at gestational day 17. - Cabazitaxel administered once daily to female rats during organogenesis at a dose of 0.16 mg/kg/day (approximately 0.02–0.06 times the Cmax in patients with cancer at the recommended human dose) caused maternal and embryofetal toxicity consisting of increased post-implantation loss, embryolethality, and fetal deaths. Decreased mean fetal birth weight associated with delays in skeletal ossification were observed at doses ≥ 0.08 mg/kg (approximately 0.02 times the Cmax at the MRHD). In utero exposure to cabazitaxel did not result in fetal abnormalities in rats or rabbits at exposure levels significantly lower than the expected human exposures. - 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. Women of childbearing potential should be advised to avoid becoming pregnant while taking Cabazitaxel. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cabazitaxel in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cabazitaxel during labor and delivery. ### Nursing Mothers - Cabazitaxel or cabazitaxel metabolites are excreted in maternal milk of lactating rats. It is not known whether this drug is excreted in human milk. Within 2 hours of a single intravenous administration of cabazitaxel to lactating rats at a dose of 0.08 mg/kg (approximately 0.02 times the maximum recommended human dose), radioactivity related to cabazitaxel was detected in the stomachs of nursing pups. This was detectable for up to 24 hours post-dose. Approximately 1.5% of the dose delivered to the mother was calculated to be delivered in the maternal milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cabazitaxel, 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 effectiveness of Cabazitaxel in pediatric patients have not been established. ### Geriatic Use - Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of cabazitaxel between patients < 65 years (n=100) and older (n=70). - Of the 371 patients with prostate cancer treated with Cabazitaxel every three weeks plus prednisone, 240 patients (64.7%) were 65 years of age and over, while 70 patients (18.9%) were 75 years of age and over. No overall differences in effectiveness were observed between patients ≥ 65 years of age and younger patients. Elderly patients (≥ 65 years of age) may be more likely to experience certain adverse reactions. The incidence of neutropenia, fatigue, asthenia, pyrexia, dizziness, urinary tract infection and dehydration occurred at rates ≥ 5% higher in patients who were 65 years of age or greater compared to younger patients ### Gender There is no FDA guidance on the use of Cabazitaxel with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cabazitaxel with respect to specific racial populations. ### Renal Impairment - No dedicated renal impairment trial for Cabazitaxel has been conducted. Based on the population pharmacokinetic analysis, no significant difference in clearance was observed in patients with mild (50 mL/min ≤ creatinine clearance (CLcr) < 80 mL/min) and moderate renal impairment (30 mL/min ≤ CLcr < 50 mL/min). No data are available for patients with severe renal impairment or end-stage renal disease . Caution should be used in patients with severe renal impairment (CLcr < 30 mL/min) and patients with end-stage renal diseases. ### Hepatic Impairment No dedicated hepatic impairment trial for Cabazitaxel has been conducted. The safety of Cabazitaxel has not been evaluated in patients with hepatic impairment . - As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations. Patients with impaired hepatic function (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN) were excluded from the randomized clinical trial. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cabazitaxel in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cabazitaxel in patients who are immunocompromised. # Administration and Monitoring ### Administration - Premedicate at least 30 minutes prior to each dose of Cabazitaxel with the following intravenous medications to reduce the risk and/or severity of hypersensitivity: - Cabazitaxel is a cytotoxic anticancer drug and caution should be exercised when handling and preparing Cabazitaxel solutions, taking into account the use of containment devices, personal protective equipment (e.g., gloves), and preparation procedures. Please refer to HANDLING AND DISPOSAL (16.3). - If Cabazitaxel Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Cabazitaxel Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with mucosa, immediately and thoroughly wash with water. - Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of Cabazitaxel infusion solution. - Read this entire section carefully before mixing and diluting. Cabazitaxel requires two dilutions prior to administration. Please follow the preparation instructions provided below, as improper preparation may lead to overdose. - Note: Both the Cabazitaxel Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the entire contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL Cabazitaxel. - The following two-step dilution process must be carried out under aseptic conditions to prepare the second (final) infusion solution. - Inspect the Cabazitaxel Injection and supplied diluent vials. The Cabazitaxel Injection is a clear yellow to brownish-yellow viscous solution. - Step 1 – First Dilution - Each vial of Cabazitaxel (cabazitaxel) 60 mg/1.5 mL must first be mixed with the entire contents of supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of Cabazitaxel. - When transferring the diluent, direct the needle onto the inside wall of Cabazitaxel vial and inject slowly to limit foaming. Remove the syringe and needle and gently mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixing of the drug and diluent. Do not shake. - Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is homogeneous and contains no visible particulate matter. It is not required that all foam dissipate prior to continuing the preparation process. - The resulting initial diluted Cabazitaxel solution (cabazitaxel 10 mg/mL) requires further dilution before administration. The second dilution should be done immediately (within 30 minutes) to obtain the final infusion as detailed in Step 2. - Step 2 – Second (Final) Dilution - Withdraw the recommended dose from the Cabazitaxel solution containing 10 mg/mL as prepared in Step 1 using a calibrated syringe and further dilute into a sterile 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. If a dose greater than 65 mg of Cabazitaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL Cabazitaxel is not exceeded. The concentration of the Cabazitaxel final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL. - Cabazitaxel should not be mixed with any other drugs. - Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle. - Cabazitaxel final infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour infusion) or within a total of 24 hours if refrigerated (including the one-hour infusion). - As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and discard. - Inspect visually for particulate matter, any crystals and discoloration prior to administration. If the Cabazitaxel first diluted solution or second (final) infusion solution is not clear or appears to have precipitation, it should be discarded. - Discard any unused portion. - The final Cabazitaxel infusion solution should be administered intravenously as a one-hour infusion at room temperature. - Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration. - The final Cabazitaxel infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions, i.e. 8 hours under ambient conditions (including the one-hour infusion) or for a total of 24 hours if refrigerated (including the one-hour infusion) ### Monitoring In order to monitor the occurrence of neutropenia, frequent blood cell counts should be performed on all patients receiving Cabazitaxel. Cabazitaxel should not be given to patients with neutrophil counts of ≤1,500 cells/mm3. # IV Compatibility There is limited information regarding IV Compatibility of Cabazitaxel in the drug label. # Overdosage - There is no known antidote for Cabazitaxel overdose. Overdose has resulted from improper preparation. Please read the entire section DOSAGE AND ADMINISTRATION (2) carefully before mixing or diluting. Complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. Overdose has led to fatal outcome. - In case of overdose, the patient should be kept in a specialized unit where vital signs, chemistry and particular functions can be closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed. # Pharmacology ## Mechanism of Action - Cabazitaxel is a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions. ## Structure - Cabazitaxel (cabazitaxel) is an antineoplastic agent belonging to the taxane class. It is prepared by semi-synthesis with a precursor extracted from yew needles. - The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3--2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one(1:1). - Cabazitaxel has the following structural formula: - Cabazitaxel is a white to almost-white powder with a molecular formula of C45H57NO14.C3H6O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol. - Cabazitaxel (cabazitaxel) Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80. - Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80. - DILUENT for Cabazitaxel is a clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL. - Cabazitaxel requires two dilutions prior to intravenous infusion. Cabazitaxel injection should be diluted only with the supplied DILUENT for Cabazitaxel, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution. ## Pharmacodynamics - Cabazitaxel demonstrated antitumor activity against advanced human tumors xenografted in mice. Cabazitaxel is active in docetaxel-sensitive tumors. In addition, cabazitaxel demonstrated activity in tumor models insensitive to chemotherapy including docetaxel. ## Pharmacokinetics - A population pharmacokinetic analysis was conducted in 170 patients with solid tumors at doses ranging from 10 to 30 mg/m2 weekly or every three weeks. - Based on the population pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m2 every three weeks, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (Tmax). The mean AUC in patients with metastatic prostate cancer was 991 ng∙h/mL (CV 34%). - No major deviation from the dose proportionality was observed from 10 to 30 mg/m2 in patients with advanced solid tumors. - The volume of distribution (Vss) was 4,864 L (2,643 L/m2 for a patient with a median BSA of 1.84 m2) at steady state. - In vitro, the binding of cabazitaxel to human serum proteins was 89 to 92% and was not saturable up to 50,000 ng/mL, which covers the maximum concentration observed in clinical trials. Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). The in vitro blood-to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, indicating that cabazitaxel was equally distributed between blood and plasma. - Cabazitaxel is extensively metabolized in the liver (> 95%), mainly by the CYP3A4/5 isoenzyme (80% to 90%), and to a lesser extent by CYP2C8. Cabazitaxel is the main circulating moiety in human plasma. Seven metabolites were detected in plasma (including the 3 active metabolites issued from O-demethylation), with the main one accounting for 5% of cabazitaxel exposure. Around 20 metabolites of cabazitaxel are excreted into human urine and feces. - After a one-hour intravenous infusion -cabazitaxel 25 mg/m2, approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine). - Based on the population pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m2 for a patient with a median BSA of 1.84 m2) in patients with metastatic prostate cancer. Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of 4 minutes, 2 hours, and 95 hours, respectively. - Cabazitaxel is minimally excreted via the kidney. No formal pharmacokinetic trials have been conducted with cabazitaxel in patients with renal impairment. The population pharmacokinetic analysis carried out in 170 patients including 14 patients with moderate renal impairment (30 mL/min ≤ CLcr < 50 mL/min) and 59 patients with mild renal impairment (50 mL/min ≤ CLcr < 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel. No data are available for patients with severe renal impairment or end-stage renal disease. - No formal trials in patients with hepatic impairment have been conducted. As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations. - A drug interaction study of Cabazitaxel in 23 patients with advanced cancers has shown that repeated administration of ketoconazole (400 mg orally once daily), a strong CYP3A inhibitor, increased the exposure to cabazitaxel (5 mg/m2 intravenous) by 25%. - A drug interaction study of Cabazitaxel in 13 patients with advanced cancers has shown that repeated administration of aprepitant (125 or 80 mg once daily), a moderate CYP3A inhibitor, did not modify the exposure to cabazitaxel (15 mg/m2 intravenous). - A drug interaction study of Cabazitaxel in 21 patients with advanced cancers has shown that repeated administration of rifampin (600 mg once daily), a strong CYP3A inducer, decreased the exposure to cabazitaxel (15 mg/m2 intravenous) by 17%. - A drug interaction study of Cabazitaxel in 11 patients with advanced cancers has shown that cabazitaxel (25 mg/m2 administered as a single 1-hour infusion) did not modify the exposure to midazolam, a probe substrate of CYP3A. - Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel. - Based on in vitro studies, the potential for cabazitaxel to inhibit drugs that are substrates of other CYP isoenzymes (1A2,-2B6,-2C9, -2C8, -2C19, -2E1, -2D6, and CYP3A4/5) is low. - In addition, cabazitaxel did not induce CYP isozymes (-1A, -2C9 and -3A) in vitro. - In vitro, cabazitaxel did not inhibit the multidrug-resistance protein 1 (MRP1) 2 (MRP2) or organic cation transporter (OCT1). In vitro, cabazitaxel inhibited P-gp, BRCP, and organic anion transporting polypeptides (OATP1B1, OATP1B3). However the in vivo risk of cabazitaxel inhibiting MRPs, OCT1, P-gp, BCRP, OATP1B1 or OATP1B3 is low at the dose of 25 mg/m2. - In vitro, cabazitaxel is a substrate of P-gp, but not a substrate of MRP1, MRP2, BCRP, OCT1, OATP1B1 or OATP1B3. - The effect of cabazitaxel following a single dose of 25 mg/m2 administered by intravenous infusion on QTc interval was evaluated in 94 patients with solid tumors. No large changes in the mean QT interval (i.e., > 20 ms) from baseline based on Fridericia correction method were detected. However, a small increase in the mean QTc interval (i.e., < 10 ms) cannot be excluded due to study design limitations. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential of cabazitaxel. - Cabazitaxel was positive for clastogenesis in the in vivo micronucleus test, inducing an increase of micronuclei in rats at doses ≥ 0.5 mg/kg. Cabazitaxel increased numerical aberrations with or without metabolic activation in an in vitro test in human lymphocytes though no induction of structural aberrations was observed. Cabazitaxel did not induce mutations in the bacterial reverse mutation (Ames) test. The positive in vivo genotoxicity findings are consistent with the pharmacological activity of the compound (inhibition of tubulin depolymerization). - Cabazitaxel may impair fertility in humans. In a fertility study performed in female rats at cabazitaxel doses of 0.05, 0.1, or 0.2 mg/kg/day there was no effect of administration of the drug on mating behavior or the ability to become pregnant. There was an increase in pre-implantation loss at the 0.2 mg/kg/day dose and an increase in early resorptions at doses ≥ 0.1 mg/kg/day (approximately 0.02–0.06 times the human clinical exposure based on Cmax). In multi-cycle studies following the clinically recommended dosing schedule, atrophy of the uterus was observed at the 5 mg/kg dose level (approximately the AUC in patients with cancer at the recommended human dose) along with necrosis of the corpora lutea at doses ≥ 1 mg/kg (approximately 0.2 times the AUC at the clinically recommended human dose). - Cabazitaxel did not affect mating performances or fertility of treated male rats at doses of 0.05, 0.1, or 0.2 mg/kg/day. In multiple-cycle studies following the clinically recommended dosing schedule, however, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats treated intravenously with cabazitaxel at a dose of 1 mg/kg (approximately 0.2–0.35 times the AUC in patients with cancer at the recommended human dose), and minimal testicular degeneration (minimal epithelial single cell necrosis in epididymis) was observed in dogs treated with a dose of 0.5 mg/kg (approximately one-tenth of the AUC in patients with cancer at the recommended human dose). # Clinical Studies - The efficacy and safety of Cabazitaxel in combination with prednisone were evaluated in a randomized, open-label, international, multi-center study in patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen. - A total of 755 patients were randomized to receive either Cabazitaxel 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone 10 mg orally daily (n=377) for a maximum of 10 cycles. - This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3, platelets > 100,000 cells/mm3, hemoglobin > 10 g/dL, creatinine < 1.5 × upper limit of normal (ULN), total bilirubin < 1×ULN, AST < 1.5 × ULN, and ALT < 1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study. - Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 46–92) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the Cabazitaxel group. - Efficacy results for the Cabazitaxel arm versus the control arm are summarized in Table 3 and Figure 1. - Investigator-assessed tumor response of 14.4% (95%CI: 9.6–19.3) was higher for patients in the Cabazitaxel arm compared to 4.4% (95%CI: 1.6–7.2) for patients in the mitoxantrone arm, p=0.0005. # How Supplied - Cabazitaxel is supplied as a kit containing one single-use vial of Cabazitaxel (cabazitaxel) Injection (clear glass vial with a grey rubber closure, aluminum cap and light green plastic flip-off cap) and one vial of Diluent for Cabazitaxel (13% (w/w) ethanol in water for injection) in a clear glass vial with a grey rubber closure, gold-color aluminum cap and colorless plastic flip-off cap. Both items are in a blister pack in one carton. ## Storage - Store at 25°C (77°F); excursions permitted between 15°–30°C (59°–86°F). - Do not refrigerate. - Stability of the First Diluted Solution in the Vial: - First diluted solution of Cabazitaxel should be used immediately (within 30 minutes). Discard any unused portion . - Stability of the Second (Final) Dilution Solution in the Infusion Bag: - Fully prepared Cabazitaxel infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour infusion), or for a total of 24 hours (including the one-hour infusion) under the refrigerated conditions. - In addition, chemical and physical stability of the infusion solution has been demonstrated for 24 hours under refrigerated conditions. As both the first diluted solution and the second (final) infusion solution are supersaturated, the solutions may crystallize over time. If crystals and/or particulates appear, the solutions must not be used and should be discarded . - Procedures for proper handling and disposal of antineoplastic drugs should be followed. Several guidelines on this subject have been published . Any unused product or waste material should be disposed of in accordance with local requirements. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL NDC 0024-5824-11 Cabazitaxel® (cabazitaxel) Injection 60 mg/1.5 mL Before First Dilution* This carton contains: 1 Cabazitaxel vial and 1 Diluent vial - Requires two dilutions before administration-See back panel for details FOR INTRAVENOUS INFUSION ONLY AFTER SECOND DILUTION CYTOTOXIC AGENT RX ONLY SANOFI Cabazitaxel® (cabazitaxel) Injection NDC 0024-5823-15 RX ONLY 60 mg/1.5 mL Before First Dilution* - FOR INTRAVENOUS INFUSION ONLY AFTER SECOND DILUTION CAUTION: Reconstitute this vial using the entire contents of the diluent vial (approx. 5.7 mL). Following this first dilution, the resultant solution contains a concentration of 10 mg/mL. Withdraw only the required amount of the first dilution to prepare the final infusion solution prior to administration. See package insert for full dilution information. Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). Do not refrigerate. Single-dose vial. CYTOTOXIC AGENT sanofi-aventis U.S. LLC / Origin France 50110242 DILUENT NDC 0024-5822-01 5.7 mL of 13 % (w/w) ethanol in water for injection. Use ONLY for dilution of Cabazitaxel. See package insert for full preparation instructions. Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). Do not refrigerate. Single-dose vial. RX ONLY sanofi-aventis U.S. LLC / Origin Germany ### Ingredients and Appearance # Patient Counseling Information - Educate patients about the risk of potential hypersensitivity associated with Cabazitaxel. Confirm patients do not have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80. Instruct patients to immediately report signs of a hypersensitivity reaction. - Explain the importance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever to the treating oncologist. - Explain that it is important to take the oral prednisone as prescribed. Instruct patients to report if they were not compliant with oral corticosteroid regimen. - Explain to patients that severe and fatal infections, dehydration, and renal failure have been associated with cabazitaxel exposure. Patients should immediately report fever, significant vomiting or diarrhea, decreased urinary output, and hematuria to the treating oncologist. - Inform patients about the risk of drug interactions and the importance of providing a list of prescription and non-prescription drugs to the treating oncologist. - Inform elderly patients that certain side effects may be more frequent or severe. ### PATIENT PACKAGE INSERT Patient Information Cabazitaxel® (JEV-TA-NA) (cabazitaxel) Injection - Read this Patient Information before you start receiving Cabazitaxel and each time before you receive your infusion. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. - Cabazitaxel may cause serious side effects including: - Low white blood cells. Low white blood cells can cause you to get serious infections, and may lead to death. People who are 65 years or older may be more likely to have these problems. Your doctor: - will do blood tests regularly to check your white blood cell counts during your treatment with Cabazitaxel. - may lower your dose of Cabazitaxel, change how often you receive it, or stop Cabazitaxel until your doctor decides that you have enough white blood cells. - may prescribe a medicine for you called G-CSF, to help prevent complications if your white blood cell count is too low. - Tell your doctor right away if you have any of these symptoms of infection while receiving Cabazitaxel: - fever. Take your temperature often during treatment with Cabazitaxel. - cough - burning on urination - muscle aches - Also, tell your doctor if you have any diarrhea during the time that your white blood cell count is low. Your doctor may prescribe treatment for you as needed. - Severe allergic reactions. Severe allergic reactions can happen within a few minutes after your infusion of Cabazitaxel starts, especially during the first and second infusions. Your doctor should prescribe medicines before each infusion to help prevent severe allergic reactions. Tell your doctor or nurse right away if you have any of these symptoms of a severe allergic reaction during or soon after an infusion of Cabazitaxel: - rash or itching - skin redness - feeling dizzy or faint - breathing problems - chest or throat tightness - swelling of face - Severe stomach and intestine (gastrointestinal) problems. Cabazitaxel can cause severe stomach and intestine problems, which may lead to death. You may need to go to the hospital for treatment. - Vomiting and diarrhea can happen when you take Cabazitaxel. Severe vomiting and diarrhea with Cabazitaxel can lead to loss of too much body fluid (dehydration), or too much of your body salts (electrolytes). Death has happened from having severe diarrhea and losing too much body fluid or body salts with Cabazitaxel. Your doctor will prescribe medicines to prevent or treat vomiting and diarrhea, as needed with Cabazitaxel. - Tell your doctor if: - you have vomiting or diarrhea - your symptoms get worse or do not get better. - Cabazitaxel can cause a leak in the stomach or intestine, intestinal blockage, infection, and bleeding in the stomach or intestine. This can lead to death. - Tell your doctor if you get any of these symptoms: - severe stomach-area (abdomen) pain - constipation - fever - blood in your stool or changes in the color of your stool. - Kidney failure. Kidney failure may happen with Cabazitaxel, because of severe infection, loss of too much body fluid (dehydration), and other reasons, which may lead to death. Your doctor will check you for this problem and treat you if needed. - Tell your doctor if you develop these signs or symptoms: - swelling of your face or body - decrease in the amount of urine that your body makes each day. - Cabazitaxel is a prescription anti-cancer medicine used with the steroid medicine prednisone. Cabazitaxel is used to treat people with prostate cancer that has worsened (progressed) after treatment with other anti-cancer medicines, including docetaxel. - It is not known if Cabazitaxel is safe and effective in children. - Do not receive Cabazitaxel if: - your white blood cell (neutrophil count) is too low - you have had a severe allergic reaction to cabazitaxel or other medicines that contain polysorbate 80. Ask your doctor if you are not sure. - Before receiving Cabazitaxel, tell your doctor if you: - had allergic reactions in the past - have kidney or liver problems - are over the age of 65 - have any other medical conditions - if you are a female and: - are pregnant or plan to become pregnant. Cabazitaxel can harm your unborn baby. Talk to your doctor about the best way for you to prevent pregnancy while you are receiving Cabazitaxel. - are breastfeeding or plan to breastfeed. It is not known if Cabazitaxel passes into your breast milk. You and your doctor should decide if you will take Cabazitaxel or breastfeed. You should not do both. - Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Cabazitaxel can interact with many other medicines. Do not take any new medicines without asking your doctor first. Your doctor will tell you if it is safe to take the new medicine with Cabazitaxel. - Cabazitaxel will be given to you by an intravenous (IV) infusion into your vein. - Your treatment will take about 1 hour. - Cabazitaxel is usually given every 3 weeks. Your doctor will decide how often you will receive Cabazitaxel . - Your doctor will also prescribe another medicine called prednisone, for you to take by mouth every day during treatment with Cabazitaxel. Your doctor will tell you how and when to take your prednisone. - It is important that you take prednisone exactly as prescribed by your doctor. If you forget to take your prednisone, or do not take it on schedule, make sure to tell your doctor or nurse. Before each infusion of Cabazitaxel, you may receive other medicines to prevent or treat side effects. - Cabazitaxel may cause serious side effects including: - See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Cabazitaxel?" - Common side effects of Cabazitaxel include: - Low red blood cell count (anemia). Your doctor will regularly check your red blood cell count. Symptoms of anemia include shortness of breath and tiredness. - Low blood platelet count. Tell your doctor if you have any unusual bruising or bleeding. - Tell your doctor if you have any side effect that bothers you or that does not go away. - These are not all the possible side effects of Cabazitaxel. For more information, ask your doctor or pharmacist. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. - This leaflet summarizes the most important information about Cabazitaxel. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Cabazitaxel that is written for health professionals. - For more information, go to www.sanofi-aventis.us or call 1-800-633-1610. - Active ingredient: cabazitaxel - Inactive ingredient: polysorbate 80 # Precautions with Alcohol - Alcohol-Cabazitaxel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - JEVTANA ® # Look-Alike Drug Names There is limited information regarding Cabazitaxel Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cabazitaxel Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [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. # Black Box Warning # Overview Cabazitaxel is a antineoplasic agent that is FDA approved for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Cabazitaxel® is a microtubule inhibitor indicated in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen. ### Dosage - The individual dosage of Cabazitaxel is based on calculation of the Body Surface Area (BSA) and is 25 mg/m2 administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout Cabazitaxel treatment. - Premedication is recommended prior to treatment. - Cabazitaxel should be administered under the supervision of a qualified physician experienced in the use of antineoplastic medicinal products. Appropriate management of complications is possible only when the adequate diagnostic and treatment facilities are readily available. - Cabazitaxel Injection single-use vial requires two dilutions prior to administration. - Do not use PVC infusion containers and polyurethane infusions sets for preparation and administration of Cabazitaxel infusion solution. - Both the Cabazitaxel Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. - The Cabazitaxel dose should be reduced if patients experience the following adverse reactions. - Discontinue Cabazitaxel treatment if a patient continues to experience any of these reactions at 20 mg/m2. - Concomitant drugs that are strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the coadministration of Cabazitaxel with these drugs. If patients require co-administration of a strong CYP3A inhibitor, consider a 25% Cabazitaxel dose reduction ### DOSAGE FORMS AND STRENGTHS - Cabazitaxel (cabazitaxel) Injection 60 mg/1.5 mL is supplied as a kit consisting of the following: - Cabazitaxel Injection 60 mg/1.5 mL: contains 60 mg cabazitaxel in 1.5 mL polysorbate 80, - Diluent for Cabazitaxel Injection 60 mg/1.5 mL: contains approximately 5.7 mL of 13% (w/w) ethanol in water for injection. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cabazitaxel in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cabazitaxel in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Cabazitaxel in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cabazitaxel in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cabazitaxel in pediatric patients. # Contraindications - Cabazitaxel should not be used in patients with neutrophil counts of ≤ 1,500/mm3. - Cabazitaxel is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80. # Warnings - Five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient's death was attributed to neutropenia without a documented infection. - G-CSF may be administered to reduce the risks of neutropenia complications associated with Cabazitaxel use. Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age > 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients considered to be at increased risk for neutropenia complications. - Monitoring of complete blood counts is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed. - Cabazitaxel should not be administered to patients with neutrophils ≤ 1,500/mm3. - If a patient experiences febrile neutropenia or prolonged neutropenia (greater than one week) despite appropriate medication (e.g., G-CSF), the dose of Cabazitaxel should be reduced. Patients can restart treatment with Cabazitaxel only when neutrophil counts recover to a level > 1,500/mm3. - All patients should be premedicated prior to the initiation of the infusion of Cabazitaxel. Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of Cabazitaxel, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of the Cabazitaxel infusion and appropriate therapy. Patients with a history of severe hypersensitivity reactions should not be re-challenged with Cabazitaxel. - Nausea, vomiting and severe diarrhea, at times, may occur. Death related to diarrhea and electrolyte imbalance occurred in the randomized clinical trial. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Patients should be treated with rehydration, anti-diarrheal or anti-emetic medications as needed. Treatment delay or dosage reduction may be necessary if patients experience Grade ≥ 3 diarrhea. - Gastrointestinal (GI) hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including fatal outcome, have been reported in patients treated with Cabazitaxel. Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, adhesions, ulceration and GI bleeding. - Abdominal pain and tenderness, fever, persistent constipation, diarrhea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. Cabazitaxel treatment delay or discontinuation may be necessary. - Renal failure, including four cases with fatal outcome, was reported in the randomized clinical trial. Most cases occurred in association with sepsis, dehydration, or obstructive uropathy. Some deaths due to renal failure did not have a clear etiology. Appropriate measures should be taken to identify causes of renal failure and treat aggressively. - In the randomized clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%) ≥ 65 years of age died of causes other than disease progression within 30 days of the last cabazitaxel dose. Patients ≥ 65 years of age are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia. - No dedicated hepatic impairment trial for Cabazitaxel has been conducted. Patients with impaired hepatic function (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN) were excluded from the randomized clinical trial. - Cabazitaxel is extensively metabolized in the liver, and hepatic impairment is likely to increase cabazitaxel concentrations. - Hepatic impairment increases the risk of severe and life-threatening complications in patients receiving other drugs belonging to the same class as Cabazitaxel. Cabazitaxel should not be given to patients with hepatic impairment (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN). - Pregnancy category D. - Cabazitaxel can cause fetal harm when administered to a pregnant woman. In non-clinical studies in rats and rabbits, cabazitaxel was embryotoxic, fetotoxic, and abortifacient at exposures significantly lower than those expected at the recommended human dose level. - There are no adequate and well-controlled studies in pregnant women using Cabazitaxel. 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. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with Cabazitaxel # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed in greater detail in another section of the label: - Neutropenia - Hypersensitivity Reactions - Gastrointestinal Disorders - Renal Failure - 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 safety of Cabazitaxel in combination with prednisone was evaluated in 371 patients with hormone-refractory metastatic prostate cancer treated in a single randomized trial, compared to mitoxantrone plus prednisone. - Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) Cabazitaxel-treated patients and 3 (< 1%) mitoxantrone-treated patients. The most common fatal adverse reactions in Cabazitaxel-treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of Cabazitaxel. Other fatal adverse reactions in Cabazitaxel-treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea. - The most common (≥ 10%) grade 1–4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysguesia, cough, arthralgia, and alopecia. - The most common (≥ 5%) grade 3–4 adverse reactions in patients who received Cabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. - Treatment discontinuations due to adverse drug reactions occurred in 18% of patients who received Cabazitaxel and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the Cabazitaxel group were neutropenia and renal failure. Dose reductions were reported in 12% of Cabazitaxel-treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of Cabazitaxel-treated patients and 15% of mitoxantrone-treated patients. - Five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient's death was attributed to neutropenia without a documented infection. Twenty-two (6%) patients discontinued Cabazitaxel treatment due to neutropenia, febrile neutropenia, infection, or sepsis. The most common adverse reaction leading to treatment discontinuation in the Cabazitaxel group was neutropenia (2%). - Adverse events of hematuria, including those requiring medical intervention, were more common in Cabazitaxel-treated patients. The incidence of grade ≥ 2 hematuria was 6% in Cabazitaxel-treated patients and 2% in mitoxantrone-treated patients. Other factors associated with hematuria were well-balanced between arms and do not account for the increased rate of hematuria on the Cabazitaxel arm. - The incidences of grade 3–4 increased AST, increased ALT, and increased bilirubin were each ≤ 1%. - The following grade 1–4 adverse reactions were reported at rates ≥ 5% higher in patients 65 years of age or greater compared to younger patients: fatigue (40% vs. 30%), neutropenia (97% vs. 89%), asthenia (24% vs. 15%), pyrexia (15% vs. 8%), dizziness (10% vs. 5%), urinary tract infection (10% vs. 3%) and dehydration (7% vs. 2%), respectively. - The incidence of the following grade 3–4 adverse reactions were higher in patients ≥ 65 years of age compared to younger patients; neutropenia (87% vs. 74%), and febrile neutropenia (8% vs. 6%) ## Postmarketing Experience - The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made. - Gastrointestinal: Gastritis, intestinal obstruction. # Drug Interactions - No formal clinical drug-drug interaction trials have been conducted with Cabazitaxel. - Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel. - CYP3A4 Inhibitors: Cabazitaxel is primarily metabolized through CYP3A. Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the co-administration of Cabazitaxel with strong CYP3A inhibitors. If patients require co-administration of a strong CYP3A inhibitor, consider a 25% Cabazitaxel dose reduction # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Cabazitaxel can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Cabazitaxel in pregnant women. - Non-clinical studies in rats and rabbits have shown that cabazitaxel is embryotoxic, fetotoxic, and abortifacient. Cabazitaxel was shown to cross the placenta barrier within 24 hours of a single intravenous administration of a 0.08 mg/kg dose (approximately 0.02 times the maximum recommended human dose-MRHD) to pregnant rats at gestational day 17. - Cabazitaxel administered once daily to female rats during organogenesis at a dose of 0.16 mg/kg/day (approximately 0.02–0.06 times the Cmax in patients with cancer at the recommended human dose) caused maternal and embryofetal toxicity consisting of increased post-implantation loss, embryolethality, and fetal deaths. Decreased mean fetal birth weight associated with delays in skeletal ossification were observed at doses ≥ 0.08 mg/kg (approximately 0.02 times the Cmax at the MRHD). In utero exposure to cabazitaxel did not result in fetal abnormalities in rats or rabbits at exposure levels significantly lower than the expected human exposures. - 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. Women of childbearing potential should be advised to avoid becoming pregnant while taking Cabazitaxel. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cabazitaxel in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cabazitaxel during labor and delivery. ### Nursing Mothers - Cabazitaxel or cabazitaxel metabolites are excreted in maternal milk of lactating rats. It is not known whether this drug is excreted in human milk. Within 2 hours of a single intravenous administration of cabazitaxel to lactating rats at a dose of 0.08 mg/kg (approximately 0.02 times the maximum recommended human dose), radioactivity related to cabazitaxel was detected in the stomachs of nursing pups. This was detectable for up to 24 hours post-dose. Approximately 1.5% of the dose delivered to the mother was calculated to be delivered in the maternal milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cabazitaxel, 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 effectiveness of Cabazitaxel in pediatric patients have not been established. ### Geriatic Use - Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of cabazitaxel between patients < 65 years (n=100) and older (n=70). - Of the 371 patients with prostate cancer treated with Cabazitaxel every three weeks plus prednisone, 240 patients (64.7%) were 65 years of age and over, while 70 patients (18.9%) were 75 years of age and over. No overall differences in effectiveness were observed between patients ≥ 65 years of age and younger patients. Elderly patients (≥ 65 years of age) may be more likely to experience certain adverse reactions. The incidence of neutropenia, fatigue, asthenia, pyrexia, dizziness, urinary tract infection and dehydration occurred at rates ≥ 5% higher in patients who were 65 years of age or greater compared to younger patients ### Gender There is no FDA guidance on the use of Cabazitaxel with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cabazitaxel with respect to specific racial populations. ### Renal Impairment - No dedicated renal impairment trial for Cabazitaxel has been conducted. Based on the population pharmacokinetic analysis, no significant difference in clearance was observed in patients with mild (50 mL/min ≤ creatinine clearance (CLcr) < 80 mL/min) and moderate renal impairment (30 mL/min ≤ CLcr < 50 mL/min). No data are available for patients with severe renal impairment or end-stage renal disease [see CLINICAL PHARMACOLOGY (12.3)]. Caution should be used in patients with severe renal impairment (CLcr < 30 mL/min) and patients with end-stage renal diseases. ### Hepatic Impairment No dedicated hepatic impairment trial for Cabazitaxel has been conducted. The safety of Cabazitaxel has not been evaluated in patients with hepatic impairment . - As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations. Patients with impaired hepatic function (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN) were excluded from the randomized clinical trial. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cabazitaxel in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cabazitaxel in patients who are immunocompromised. # Administration and Monitoring ### Administration - Premedicate at least 30 minutes prior to each dose of Cabazitaxel with the following intravenous medications to reduce the risk and/or severity of hypersensitivity: - Cabazitaxel is a cytotoxic anticancer drug and caution should be exercised when handling and preparing Cabazitaxel solutions, taking into account the use of containment devices, personal protective equipment (e.g., gloves), and preparation procedures. Please refer to HANDLING AND DISPOSAL (16.3). - If Cabazitaxel Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Cabazitaxel Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with mucosa, immediately and thoroughly wash with water. - Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of Cabazitaxel infusion solution. - Read this entire section carefully before mixing and diluting. Cabazitaxel requires two dilutions prior to administration. Please follow the preparation instructions provided below, as improper preparation may lead to overdose. - Note: Both the Cabazitaxel Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the entire contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL Cabazitaxel. - The following two-step dilution process must be carried out under aseptic conditions to prepare the second (final) infusion solution. - Inspect the Cabazitaxel Injection and supplied diluent vials. The Cabazitaxel Injection is a clear yellow to brownish-yellow viscous solution. - Step 1 – First Dilution - Each vial of Cabazitaxel (cabazitaxel) 60 mg/1.5 mL must first be mixed with the entire contents of supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of Cabazitaxel. - When transferring the diluent, direct the needle onto the inside wall of Cabazitaxel vial and inject slowly to limit foaming. Remove the syringe and needle and gently mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixing of the drug and diluent. Do not shake. - Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is homogeneous and contains no visible particulate matter. It is not required that all foam dissipate prior to continuing the preparation process. - The resulting initial diluted Cabazitaxel solution (cabazitaxel 10 mg/mL) requires further dilution before administration. The second dilution should be done immediately (within 30 minutes) to obtain the final infusion as detailed in Step 2. - Step 2 – Second (Final) Dilution - Withdraw the recommended dose from the Cabazitaxel solution containing 10 mg/mL as prepared in Step 1 using a calibrated syringe and further dilute into a sterile 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. If a dose greater than 65 mg of Cabazitaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL Cabazitaxel is not exceeded. The concentration of the Cabazitaxel final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL. - Cabazitaxel should not be mixed with any other drugs. - Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle. - Cabazitaxel final infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour infusion) or within a total of 24 hours if refrigerated (including the one-hour infusion). - As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and discard. - Inspect visually for particulate matter, any crystals and discoloration prior to administration. If the Cabazitaxel first diluted solution or second (final) infusion solution is not clear or appears to have precipitation, it should be discarded. - Discard any unused portion. - The final Cabazitaxel infusion solution should be administered intravenously as a one-hour infusion at room temperature. - Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration. - The final Cabazitaxel infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions, i.e. 8 hours under ambient conditions (including the one-hour infusion) or for a total of 24 hours if refrigerated (including the one-hour infusion) ### Monitoring In order to monitor the occurrence of neutropenia, frequent blood cell counts should be performed on all patients receiving Cabazitaxel. Cabazitaxel should not be given to patients with neutrophil counts of ≤1,500 cells/mm3. # IV Compatibility There is limited information regarding IV Compatibility of Cabazitaxel in the drug label. # Overdosage - There is no known antidote for Cabazitaxel overdose. Overdose has resulted from improper preparation. Please read the entire section DOSAGE AND ADMINISTRATION (2) carefully before mixing or diluting. Complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. Overdose has led to fatal outcome. - In case of overdose, the patient should be kept in a specialized unit where vital signs, chemistry and particular functions can be closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed. # Pharmacology ## Mechanism of Action - Cabazitaxel is a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions. ## Structure - Cabazitaxel (cabazitaxel) is an antineoplastic agent belonging to the taxane class. It is prepared by semi-synthesis with a precursor extracted from yew needles. - The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one(1:1). - Cabazitaxel has the following structural formula: - Cabazitaxel is a white to almost-white powder with a molecular formula of C45H57NO14.C3H6O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol. - Cabazitaxel (cabazitaxel) Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80. - Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80. - DILUENT for Cabazitaxel is a clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL. - Cabazitaxel requires two dilutions prior to intravenous infusion. Cabazitaxel injection should be diluted only with the supplied DILUENT for Cabazitaxel, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution. ## Pharmacodynamics - Cabazitaxel demonstrated antitumor activity against advanced human tumors xenografted in mice. Cabazitaxel is active in docetaxel-sensitive tumors. In addition, cabazitaxel demonstrated activity in tumor models insensitive to chemotherapy including docetaxel. ## Pharmacokinetics - A population pharmacokinetic analysis was conducted in 170 patients with solid tumors at doses ranging from 10 to 30 mg/m2 weekly or every three weeks. - Based on the population pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m2 every three weeks, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (Tmax). The mean AUC in patients with metastatic prostate cancer was 991 ng∙h/mL (CV 34%). - No major deviation from the dose proportionality was observed from 10 to 30 mg/m2 in patients with advanced solid tumors. - The volume of distribution (Vss) was 4,864 L (2,643 L/m2 for a patient with a median BSA of 1.84 m2) at steady state. - In vitro, the binding of cabazitaxel to human serum proteins was 89 to 92% and was not saturable up to 50,000 ng/mL, which covers the maximum concentration observed in clinical trials. Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). The in vitro blood-to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, indicating that cabazitaxel was equally distributed between blood and plasma. - Cabazitaxel is extensively metabolized in the liver (> 95%), mainly by the CYP3A4/5 isoenzyme (80% to 90%), and to a lesser extent by CYP2C8. Cabazitaxel is the main circulating moiety in human plasma. Seven metabolites were detected in plasma (including the 3 active metabolites issued from O-demethylation), with the main one accounting for 5% of cabazitaxel exposure. Around 20 metabolites of cabazitaxel are excreted into human urine and feces. - After a one-hour intravenous infusion [14C]-cabazitaxel 25 mg/m2, approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine). - Based on the population pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m2 for a patient with a median BSA of 1.84 m2) in patients with metastatic prostate cancer. Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of 4 minutes, 2 hours, and 95 hours, respectively. - Cabazitaxel is minimally excreted via the kidney. No formal pharmacokinetic trials have been conducted with cabazitaxel in patients with renal impairment. The population pharmacokinetic analysis carried out in 170 patients including 14 patients with moderate renal impairment (30 mL/min ≤ CLcr < 50 mL/min) and 59 patients with mild renal impairment (50 mL/min ≤ CLcr < 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel. No data are available for patients with severe renal impairment or end-stage renal disease. - No formal trials in patients with hepatic impairment have been conducted. As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations. - A drug interaction study of Cabazitaxel in 23 patients with advanced cancers has shown that repeated administration of ketoconazole (400 mg orally once daily), a strong CYP3A inhibitor, increased the exposure to cabazitaxel (5 mg/m2 intravenous) by 25%. - A drug interaction study of Cabazitaxel in 13 patients with advanced cancers has shown that repeated administration of aprepitant (125 or 80 mg once daily), a moderate CYP3A inhibitor, did not modify the exposure to cabazitaxel (15 mg/m2 intravenous). - A drug interaction study of Cabazitaxel in 21 patients with advanced cancers has shown that repeated administration of rifampin (600 mg once daily), a strong CYP3A inducer, decreased the exposure to cabazitaxel (15 mg/m2 intravenous) by 17%. - A drug interaction study of Cabazitaxel in 11 patients with advanced cancers has shown that cabazitaxel (25 mg/m2 administered as a single 1-hour infusion) did not modify the exposure to midazolam, a probe substrate of CYP3A. - Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel. - Based on in vitro studies, the potential for cabazitaxel to inhibit drugs that are substrates of other CYP isoenzymes (1A2,-2B6,-2C9, -2C8, -2C19, -2E1, -2D6, and CYP3A4/5) is low. - In addition, cabazitaxel did not induce CYP isozymes (-1A, -2C9 and -3A) in vitro. - In vitro, cabazitaxel did not inhibit the multidrug-resistance protein 1 (MRP1) 2 (MRP2) or organic cation transporter (OCT1). In vitro, cabazitaxel inhibited P-gp, BRCP, and organic anion transporting polypeptides (OATP1B1, OATP1B3). However the in vivo risk of cabazitaxel inhibiting MRPs, OCT1, P-gp, BCRP, OATP1B1 or OATP1B3 is low at the dose of 25 mg/m2. - In vitro, cabazitaxel is a substrate of P-gp, but not a substrate of MRP1, MRP2, BCRP, OCT1, OATP1B1 or OATP1B3. - The effect of cabazitaxel following a single dose of 25 mg/m2 administered by intravenous infusion on QTc interval was evaluated in 94 patients with solid tumors. No large changes in the mean QT interval (i.e., > 20 ms) from baseline based on Fridericia correction method were detected. However, a small increase in the mean QTc interval (i.e., < 10 ms) cannot be excluded due to study design limitations. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential of cabazitaxel. - Cabazitaxel was positive for clastogenesis in the in vivo micronucleus test, inducing an increase of micronuclei in rats at doses ≥ 0.5 mg/kg. Cabazitaxel increased numerical aberrations with or without metabolic activation in an in vitro test in human lymphocytes though no induction of structural aberrations was observed. Cabazitaxel did not induce mutations in the bacterial reverse mutation (Ames) test. The positive in vivo genotoxicity findings are consistent with the pharmacological activity of the compound (inhibition of tubulin depolymerization). - Cabazitaxel may impair fertility in humans. In a fertility study performed in female rats at cabazitaxel doses of 0.05, 0.1, or 0.2 mg/kg/day there was no effect of administration of the drug on mating behavior or the ability to become pregnant. There was an increase in pre-implantation loss at the 0.2 mg/kg/day dose and an increase in early resorptions at doses ≥ 0.1 mg/kg/day (approximately 0.02–0.06 times the human clinical exposure based on Cmax). In multi-cycle studies following the clinically recommended dosing schedule, atrophy of the uterus was observed at the 5 mg/kg dose level (approximately the AUC in patients with cancer at the recommended human dose) along with necrosis of the corpora lutea at doses ≥ 1 mg/kg (approximately 0.2 times the AUC at the clinically recommended human dose). - Cabazitaxel did not affect mating performances or fertility of treated male rats at doses of 0.05, 0.1, or 0.2 mg/kg/day. In multiple-cycle studies following the clinically recommended dosing schedule, however, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats treated intravenously with cabazitaxel at a dose of 1 mg/kg (approximately 0.2–0.35 times the AUC in patients with cancer at the recommended human dose), and minimal testicular degeneration (minimal epithelial single cell necrosis in epididymis) was observed in dogs treated with a dose of 0.5 mg/kg (approximately one-tenth of the AUC in patients with cancer at the recommended human dose). # Clinical Studies - The efficacy and safety of Cabazitaxel in combination with prednisone were evaluated in a randomized, open-label, international, multi-center study in patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen. - A total of 755 patients were randomized to receive either Cabazitaxel 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone 10 mg orally daily (n=377) for a maximum of 10 cycles. - This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3, platelets > 100,000 cells/mm3, hemoglobin > 10 g/dL, creatinine < 1.5 × upper limit of normal (ULN), total bilirubin < 1×ULN, AST < 1.5 × ULN, and ALT < 1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study. - Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 46–92) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the Cabazitaxel group. - Efficacy results for the Cabazitaxel arm versus the control arm are summarized in Table 3 and Figure 1. - Investigator-assessed tumor response of 14.4% (95%CI: 9.6–19.3) was higher for patients in the Cabazitaxel arm compared to 4.4% (95%CI: 1.6–7.2) for patients in the mitoxantrone arm, p=0.0005. # How Supplied - Cabazitaxel is supplied as a kit containing one single-use vial of Cabazitaxel (cabazitaxel) Injection (clear glass vial with a grey rubber closure, aluminum cap and light green plastic flip-off cap) and one vial of Diluent for Cabazitaxel (13% (w/w) ethanol in water for injection) in a clear glass vial with a grey rubber closure, gold-color aluminum cap and colorless plastic flip-off cap. Both items are in a blister pack in one carton. ## Storage - Store at 25°C (77°F); excursions permitted between 15°–30°C (59°–86°F). - Do not refrigerate. - Stability of the First Diluted Solution in the Vial: - First diluted solution of Cabazitaxel should be used immediately (within 30 minutes). Discard any unused portion . - Stability of the Second (Final) Dilution Solution in the Infusion Bag: - Fully prepared Cabazitaxel infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour infusion), or for a total of 24 hours (including the one-hour infusion) under the refrigerated conditions. - In addition, chemical and physical stability of the infusion solution has been demonstrated for 24 hours under refrigerated conditions. As both the first diluted solution and the second (final) infusion solution are supersaturated, the solutions may crystallize over time. If crystals and/or particulates appear, the solutions must not be used and should be discarded [see DOSAGE AND ADMINISTRATION (2.5)]. - Procedures for proper handling and disposal of antineoplastic drugs should be followed. Several guidelines on this subject have been published [see REFERENCES (15)]. Any unused product or waste material should be disposed of in accordance with local requirements. # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL NDC 0024-5824-11 Cabazitaxel® (cabazitaxel) Injection 60 mg/1.5 mL Before First Dilution* This carton contains: 1 Cabazitaxel vial and 1 Diluent vial - Requires two dilutions before administration-See back panel for details FOR INTRAVENOUS INFUSION ONLY AFTER SECOND DILUTION CYTOTOXIC AGENT RX ONLY SANOFI Cabazitaxel® (cabazitaxel) Injection NDC 0024-5823-15 RX ONLY 60 mg/1.5 mL Before First Dilution* - FOR INTRAVENOUS INFUSION ONLY AFTER SECOND DILUTION CAUTION: Reconstitute this vial using the entire contents of the diluent vial (approx. 5.7 mL). Following this first dilution, the resultant solution contains a concentration of 10 mg/mL. Withdraw only the required amount of the first dilution to prepare the final infusion solution prior to administration. See package insert for full dilution information. Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). Do not refrigerate. Single-dose vial. CYTOTOXIC AGENT sanofi-aventis U.S. LLC / Origin France 50110242 <MAT>526223 DILUENT NDC 0024-5822-01 5.7 mL of 13 % (w/w) ethanol in water for injection. Use ONLY for dilution of Cabazitaxel. See package insert for full preparation instructions. Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). Do not refrigerate. Single-dose vial. RX ONLY sanofi-aventis U.S. LLC / Origin Germany 50110243 <MAT>526222 ### Ingredients and Appearance # Patient Counseling Information - Educate patients about the risk of potential hypersensitivity associated with Cabazitaxel. Confirm patients do not have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80. Instruct patients to immediately report signs of a hypersensitivity reaction. - Explain the importance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever to the treating oncologist. - Explain that it is important to take the oral prednisone as prescribed. Instruct patients to report if they were not compliant with oral corticosteroid regimen. - Explain to patients that severe and fatal infections, dehydration, and renal failure have been associated with cabazitaxel exposure. Patients should immediately report fever, significant vomiting or diarrhea, decreased urinary output, and hematuria to the treating oncologist. - Inform patients about the risk of drug interactions and the importance of providing a list of prescription and non-prescription drugs to the treating oncologist. - Inform elderly patients that certain side effects may be more frequent or severe. ### PATIENT PACKAGE INSERT Patient Information Cabazitaxel® (JEV-TA-NA) (cabazitaxel) Injection - Read this Patient Information before you start receiving Cabazitaxel and each time before you receive your infusion. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. - Cabazitaxel may cause serious side effects including: - Low white blood cells. Low white blood cells can cause you to get serious infections, and may lead to death. People who are 65 years or older may be more likely to have these problems. Your doctor: - will do blood tests regularly to check your white blood cell counts during your treatment with Cabazitaxel. - may lower your dose of Cabazitaxel, change how often you receive it, or stop Cabazitaxel until your doctor decides that you have enough white blood cells. - may prescribe a medicine for you called G-CSF, to help prevent complications if your white blood cell count is too low. - Tell your doctor right away if you have any of these symptoms of infection while receiving Cabazitaxel: - fever. Take your temperature often during treatment with Cabazitaxel. - cough - burning on urination - muscle aches - Also, tell your doctor if you have any diarrhea during the time that your white blood cell count is low. Your doctor may prescribe treatment for you as needed. - Severe allergic reactions. Severe allergic reactions can happen within a few minutes after your infusion of Cabazitaxel starts, especially during the first and second infusions. Your doctor should prescribe medicines before each infusion to help prevent severe allergic reactions. Tell your doctor or nurse right away if you have any of these symptoms of a severe allergic reaction during or soon after an infusion of Cabazitaxel: - rash or itching - skin redness - feeling dizzy or faint - breathing problems - chest or throat tightness - swelling of face - Severe stomach and intestine (gastrointestinal) problems. Cabazitaxel can cause severe stomach and intestine problems, which may lead to death. You may need to go to the hospital for treatment. - Vomiting and diarrhea can happen when you take Cabazitaxel. Severe vomiting and diarrhea with Cabazitaxel can lead to loss of too much body fluid (dehydration), or too much of your body salts (electrolytes). Death has happened from having severe diarrhea and losing too much body fluid or body salts with Cabazitaxel. Your doctor will prescribe medicines to prevent or treat vomiting and diarrhea, as needed with Cabazitaxel. - Tell your doctor if: - you have vomiting or diarrhea - your symptoms get worse or do not get better. - Cabazitaxel can cause a leak in the stomach or intestine, intestinal blockage, infection, and bleeding in the stomach or intestine. This can lead to death. - Tell your doctor if you get any of these symptoms: - severe stomach-area (abdomen) pain - constipation - fever - blood in your stool or changes in the color of your stool. - Kidney failure. Kidney failure may happen with Cabazitaxel, because of severe infection, loss of too much body fluid (dehydration), and other reasons, which may lead to death. Your doctor will check you for this problem and treat you if needed. - Tell your doctor if you develop these signs or symptoms: - swelling of your face or body - decrease in the amount of urine that your body makes each day. - Cabazitaxel is a prescription anti-cancer medicine used with the steroid medicine prednisone. Cabazitaxel is used to treat people with prostate cancer that has worsened (progressed) after treatment with other anti-cancer medicines, including docetaxel. - It is not known if Cabazitaxel is safe and effective in children. - Do not receive Cabazitaxel if: - your white blood cell (neutrophil count) is too low - you have had a severe allergic reaction to cabazitaxel or other medicines that contain polysorbate 80. Ask your doctor if you are not sure. - Before receiving Cabazitaxel, tell your doctor if you: - had allergic reactions in the past - have kidney or liver problems - are over the age of 65 - have any other medical conditions - if you are a female and: - are pregnant or plan to become pregnant. Cabazitaxel can harm your unborn baby. Talk to your doctor about the best way for you to prevent pregnancy while you are receiving Cabazitaxel. - are breastfeeding or plan to breastfeed. It is not known if Cabazitaxel passes into your breast milk. You and your doctor should decide if you will take Cabazitaxel or breastfeed. You should not do both. - Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Cabazitaxel can interact with many other medicines. Do not take any new medicines without asking your doctor first. Your doctor will tell you if it is safe to take the new medicine with Cabazitaxel. - Cabazitaxel will be given to you by an intravenous (IV) infusion into your vein. - Your treatment will take about 1 hour. - Cabazitaxel is usually given every 3 weeks. Your doctor will decide how often you will receive Cabazitaxel . - Your doctor will also prescribe another medicine called prednisone, for you to take by mouth every day during treatment with Cabazitaxel. Your doctor will tell you how and when to take your prednisone. - It is important that you take prednisone exactly as prescribed by your doctor. If you forget to take your prednisone, or do not take it on schedule, make sure to tell your doctor or nurse. Before each infusion of Cabazitaxel, you may receive other medicines to prevent or treat side effects. - Cabazitaxel may cause serious side effects including: - See "WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT Cabazitaxel?" - Common side effects of Cabazitaxel include: - Low red blood cell count (anemia). Your doctor will regularly check your red blood cell count. Symptoms of anemia include shortness of breath and tiredness. - Low blood platelet count. Tell your doctor if you have any unusual bruising or bleeding. - Tell your doctor if you have any side effect that bothers you or that does not go away. - These are not all the possible side effects of Cabazitaxel. For more information, ask your doctor or pharmacist. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. - This leaflet summarizes the most important information about Cabazitaxel. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Cabazitaxel that is written for health professionals. - For more information, go to www.sanofi-aventis.us or call 1-800-633-1610. - Active ingredient: cabazitaxel - Inactive ingredient: polysorbate 80 # Precautions with Alcohol - Alcohol-Cabazitaxel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - JEVTANA ®[1] # Look-Alike Drug Names There is limited information regarding Cabazitaxel Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cabazitaxel
8ef391351a51b652926d6b6c0f379f74ba7fc41c	wikidoc	Cabergoline	Cabergoline # 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 Cabergoline is a dopamine receptor agonist that is FDA approved for the {{{indicationType}}} of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas. Common adverse reactions include constipation, nausea, dizziness, headache and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dosage of cabergoline tablets for initiation of therapy is 0.25 mg twice a week. Dosage may be increased by 0.25 mg twice weekly up to a dosage of 1 mg twice a week according to the patient’s serum prolactin level. Before initiating treatment, cardiovascular evaluation should be performed and echocardiography should be considered to assess for valvular disease. - Dosage increases should not occur more rapidly than every 4 weeks, so that the physician can assess the patient’s response to each dosage level. If the patient does not respond adequately, and no additional benefit is observed with higher doses, the lowest dose that achieved maximal response should be used and other therapeutic approaches considered. Patients receiving long-term treatment with cabergoline should undergo periodic assessment of their cardiac status and echocardiography should be considered. - After a normal serum prolactin level has been maintained for 6 months, cabergoline may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with cabergoline should be reinstituted. The durability of efficacy beyond 24 months of therapy with cabergoline has not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cabergoline in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Cabergoline was given to patients not cured by prior therapy or as primary treatment. It was started at 0.5 milligrams (mg) twice weekly. The dose was increased, as needed, to 0.5 mg every 2 days (1.75 mg/week) - Dosing Information - Cabergoline 0.5 milligrams (mg) twice weekly for 4 months. - Dosing Information - Cabergoline 0.6 to 1 milligram as a single oral dose. - Dosing Information - Cabergoline at a maximum dose of 4 milligrams once daily either as monotherapy, or in association with levodopa/carbidopa. - Dosing Information - Cabergoline was initiated at 0.5 milligrams (mg)/day, with target doses ranging from 2 to 3 mg/day. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Cabergoline in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cabergoline in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cabergoline in pediatric patients. # Contraindications - Cabergoline tablets are contraindicated in patients with - Uncontrolled hypertension or known hypersensitivity to ergot derivatives. History of cardiac valvular disorders, as suggested by anatomical evidence of valvulopathy of any valve, determined by pre-treatment evaluation including echocardiographic demonstration of valve leaflet thickening, valve restriction, or mixed valve restriction-stenosis. History of pulmonary, pericardial, or retroperitoneal fibrotic disorders. - Uncontrolled hypertension or known hypersensitivity to ergot derivatives. - History of cardiac valvular disorders, as suggested by anatomical evidence of valvulopathy of any valve, determined by pre-treatment evaluation including echocardiographic demonstration of valve leaflet thickening, valve restriction, or mixed valve restriction-stenosis. - History of pulmonary, pericardial, or retroperitoneal fibrotic disorders. # Warnings ### Precautions - Pregnancy - Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia, eclampsia, and post partum hypertension, unless the potential benefit is judged to outweigh the possible risk. - Fibrotic Complications - Cardiac Valvulopathy - All patients should undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of valvular disease. If valvular disease is detected, the patient should not be treated with cabergoline. Postmarketing cases of cardiac valvulopathy have been reported in patients receiving cabergoline. These cases have generally occurred during administration of high doses of cabergoline (> 2 mg/day) for the treatment of Parkinson’s disease. Cases of cardiac valvulopathy have also been reported in patients receiving lower doses of cabergoline for the treatment of hyperprolactinemic disorders. - A multi-country, retrospective cohort study using general practice records and record linkage systems in the UK, Italy and the Netherlands was conducted to assess the association between new use of dopamine agonists including cabergoline (n = 27,812) for Parkinson’s disease and hyperprolactinemia and cardiac valvular regurgitation (CVR), other fibroses, and other cardiopulmonary events over a maximum of 12 years of follow up. In this study, the use of cabergoline among persons with Parkinson's disease was associated with an increased risk of CVR when compared to non-ergot-derived dopamine agonists (DAs) and levodopa . In the study analysis confined to persons with dopamine agonist-treated hyperprolactinemia (n = 8,386), when compared to non-use (n = 15,147), persons exposed to cabergoline did not have an elevated risk of CVR. The findings with respect to the risk of CVR associated with cabergoline treatment for persons with Parkinson’s disease (increased risk) and those with hyperprolactinemia (no increased risk) are consistent with the findings in other published studies. - Physicians should use the lowest effective dose of cabergoline for the treatment of hyperprolactinemic disorders and should periodically reassess the need for continuing therapy with cabergoline. Following treatment initiation, clinical and diagnostic monitoring (for example, chest x-ray, CT scan and cardiac echocardiogram) should be conducted to assess the risk of cardiac valvulopathy. The recommended frequency of routine echocardiographic monitoring is every 6 to 12 months or as clinically indicated with the presence of signs and symptoms such as edema, new cardiac murmur, dyspnea, or congestive heart failure. - Cabergoline should be discontinued if an echocardiogram reveals new valvular regurgitation, valvular restriction or valve leaflet thickening. - Cabergoline should be used with caution in patients exposed to other medications associated with valvulopathy. - Extracardiac Fibrotic Reactions - Postmarketing cases of pleural, pericardial, and retroperitoneal fibrosis have been reported following administration of cabergoline. Some reports were in patients previously treated with other ergotinic dopamine agonists. Cabergoline should not be used in patients with a history of cardiac or extracardiac fibrotic disorders. - Fibrotic disorders can have an insidious onset and patients should be monitored for manifestations of progressive fibrosis. Therefore, during treatment, attention should be paid to the signs and symptoms of: Pleuro-pulmonary disease such as dyspnea, shortness of breath, persistent cough or chest pain. Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb edema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis. Cardiac failure: Cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur. - Pleuro-pulmonary disease such as dyspnea, shortness of breath, persistent cough or chest pain. - Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb edema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis. - Cardiac failure: Cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur. - Clinical and diagnostic monitoring such as erythrocyte sedimentation rate, chest x-ray, serum creatinine measurements, and other investigations should be considered at baseline and as necessary while patients are treated with cabergoline. - Following diagnosis of pleural effusion or pulmonary fibrosis, the discontinuance of cabergoline was reported to result in improvement of signs and symptoms. - General - Initial doses higher than 1 mg may produce orthostatic hypotension. Care should be exercised when administering cabergoline with other medications known to lower blood pressure. - Postpartum Lactation Inhibition or Suppression - Cabergoline tablets are not indicated for the inhibition or suppression of physiologic lactation. Use of bromocriptine, another dopamine agonist for this purpose, has been associated with cases of hypertension, stroke, and seizures. - Hepatic Impairment - Since cabergoline is extensively metabolized by the liver, caution should be used, and careful monitoring exercised, when administering cabergoline to patients with hepatic impairment. - Psychiatric - Pathological gambling, increased libido, and hypersexuality have been reported in patients treated with dopamine agonists including cabergoline. This has been generally reversible upon reduction of the dose or treatment discontinuation. # Adverse Reactions ## Clinical Trials Experience - The safety of cabergoline tablets has been evaluated in more than 900 patients with hyperprolactinemic disorders. Most adverse events were mild or moderate in severity. - In a 4 week, double-blind, placebo-controlled study, treatment consisted of placebo or cabergoline at fixed doses of 0.125, 0.5, 0.75, or 1 mg twice weekly. Doses were halved during the first week. Since a possible dose-related effect was observed for nausea only, the four cabergoline treatment groups have been combined. The incidence of the most common adverse events during the placebo-controlled study is presented in the following table. - In the 8 week, double-blind period of the comparative trial with bromocriptine, cabergoline (at a dose of 0.5 mg twice weekly) was discontinued because of an adverse event in 4 of 221 patients (2%) while bromocriptine (at a dose of 2.5 mg two times a day) was discontinued in 14 of 231 patients (6%). The most common reasons for discontinuation from cabergoline were headache, nausea and vomiting (3, 2 and 2 patients respectively); the most common reasons for discontinuation from bromocriptine were nausea, vomiting, headache, and dizziness or vertigo (10, 3, 3, and 3 patients respectively). The incidence of the most common adverse events during the double-blind portion of the comparative trial with bromocriptine is presented in the following table. - Other adverse events that were reported at an incidence of < 1% in the overall clinical studies follow. Facial edema, influenza-like symptoms, malaise Hypotension, syncope, palpitations Dry mouth, flatulence, diarrhea, anorexia Weight loss, weight gain Somnolence, nervousness, paresthesia, insomnia, anxiety Nasal stuffiness, epistaxis Acne, pruritus Abnormal vision Dysmenorrhea, increased libido - The safety of cabergoline has been evaluated in approximately 1,200 patients with Parkinson’s disease in controlled and uncontrolled studies at dosages of up to 11.5 mg/day which greatly exceeds the maximum recommended dosage of cabergoline for hyperprolactinemic disorders. In addition to the adverse events that occurred in the patients with hyperprolactinemic disorders, the most common adverse events in patients with Parkinson’s disease were dyskinesia, hallucinations, confusion, and peripheral edema. Heart failure, pleural effusion, pulmonary fibrosis, and gastric or duodenal ulcer occurred rarely. One case of constrictive pericarditis has been reported. ## Postmarketing Experience - The following events have been reported in association with cabergoline: cardiac valvulopathy and extracardiac fibrotic reactions. - Other events have been reported in association with cabergoline: hypersexuality, increased libido, pathological gambling. In addition, cases of alopecia, aggression and psychotic disorder have been reported in patients taking cabergoline. Some of these reports have been in patients who have had prior adverse reactions to dopamine agonist products. # Drug Interactions - Cabergoline should not be administered concurrently with D2-antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed with cabergoline in mice, rats, and rabbits administered by gavage. - (Multiples of the maximum recommended human dose in this section are calculated on a body surface area basis using total mg/m2/week for animals and mg/m2/week for a 50 kg human.) - There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis. - A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in post-implantation embryofetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose). - In rats, doses higher than 0.003 mg/kg/day (approximately 1/28 the maximum recommended human dose) from 6 days before parturition and throughout the lactation period inhibited growth and caused death of offspring due to decreased milk secretion. - 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): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cabergoline in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cabergoline 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 cabergoline, 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. Use of cabergoline for the inhibition or suppression of physiologic lactation is not recommended (see PRECAUTIONS section). - The prolactin-lowering action of cabergoline suggests that it will interfere with lactation. Due to this interference with lactation, cabergoline should not be given to women postpartum who are breastfeeding or who are planning to breastfeed. ### Pediatric Use - Safety and effectiveness of cabergoline in pediatric patients have not been established. ### Geriatic Use - Clinical studies of cabergoline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. 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, usually starting at the low end of the dosing range, 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 Cabergoline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cabergoline with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Cabergoline in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Cabergoline in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cabergoline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cabergoline in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Cabergoline in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Cabergoline in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. ### Management - Measures to support blood pressure should be taken if necessary. ## Chronic Overdose There is limited information regarding Chronic Overdose of Cabergoline in the drug label. # Pharmacology ## Mechanism of Action - The secretion of prolactin by the anterior pituitary is mainly under hypothalamic inhibitory control, likely exerted through release of dopamine by tuberoinfundibular neurons. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Results of in vitro studies demonstrate that cabergoline exerts a direct inhibitory effect on the secretion of prolactin by rat pituitary lactotrophs. Cabergoline decreased serum prolactin levels in reserpinized rats. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D1, α1- and α2-adrenergic, and 5-HT1- and 5-HT2-serotonin receptors. ## Structure - Cabergoline Tablets USP contain cabergoline, USP, a dopamine receptor agonist. The chemical name for cabergoline, USP is 1--1--3-ethylurea and has the following structural formula: - Cabergoline, USP is a white powder soluble in ethyl alcohol, chloroform, and N, N-dimethylformamide (DMF); slightly soluble in 0.1N hydrochloric acid; very slightly soluble in n-hexane; and insoluble in water. - Each Cabergoline Tablet USP, for oral administration, contains 0.5 mg of cabergoline, USP and has the following inactive ingredients: anhydrous lactose and leucine. ## Pharmacodynamics - Dose response with inhibition of plasma prolactin, onset of maximal effect, and duration of effect has been documented following single cabergoline doses to healthy volunteers (0.05 to 1.5 mg) and hyperprolactinemic patients (0.3 to 1 mg). In volunteers, prolactin inhibition was evident at doses > 0.2 mg, while doses ≥ 0.5 mg caused maximal suppression in most subjects. Higher doses produce prolactin suppression in a greater proportion of subjects and with an earlier onset and longer duration of action. In 12 healthy volunteers, 0.5, 1, and 1.5 mg doses resulted in complete prolactin inhibition, with a maximum effect within 3 hours in 92% to 100% of subjects after the 1 and 1.5 mg doses compared with 50% of subjects after the 0.5 mg dose. - In hyperprolactinemic patients (N = 51), the maximal prolactin decrease after a 0.6 mg single dose of cabergoline was comparable to 2.5 mg bromocriptine; however, the duration of effect was markedly longer (14 days vs. 24 hours). The time to maximal effect was shorter for bromocriptine than cabergoline (6 hours vs. 48 hours). - In 72 healthy volunteers, single or multiple doses (up to 2 mg) of cabergoline resulted in selective inhibition of prolactin with no apparent effect on other anterior pituitary hormones (GH, FSH, LH, ACTH, and TSH) or cortisol. ## Pharmacokinetics - Absorption - Following single oral doses of 0.5 mg to 1.5 mg given to 12 healthy adult volunteers, mean peak plasma levels of 30 to 70 picograms (pg)/mL of cabergoline were observed within 2 to 3 hours. Over the 0.5 to 7 mg dose range, cabergoline plasma levels appeared to be dose-proportional in 12 healthy adult volunteers and nine adult parkinsonian patients. A repeat-dose study in 12 healthy volunteers suggests that steady-state levels following a once-weekly dosing schedule are expected to be two-fold to three-fold higher than after a single dose. The absolute bioavailability of cabergoline is unknown. A significant fraction of the administered dose undergoes a first-pass effect. The elimination half-life of cabergoline estimated from urinary data of 12 healthy subjects ranged between 63 to 69 hours. The prolonged prolactin-lowering effect of cabergoline may be related to its slow elimination and long half-life. - Distribution - In animals, based on total radioactivity, cabergoline (and/or its metabolites) has shown extensive tissue distribution. Radioactivity in the pituitary exceeded that in plasma by > 100 fold and was eliminated with a half-life of approximately 60 hours. This finding is consistent with the long-lasting prolactin-lowering effect of the drug. Whole body autoradiography studies in pregnant rats showed no fetal uptake but high levels in the uterine wall. Significant radioactivity (parent plus metabolites) detected in the milk of lactating rats suggests a potential for exposure to nursing infants. The drug is extensively distributed throughout the body. Cabergoline is moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. Concomitant dosing of highly protein-bound drugs is unlikely to affect its disposition. - Metabolism - In both animals and humans, cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond or the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. Cabergoline does not cause enzyme induction and/or inhibition in the rat. Hydrolysis of the acylurea or urea moiety abolishes the prolactin-lowering effect of cabergoline, and major metabolites identified thus far do not contribute to the therapeutic effect. - Excretion - After oral dosing of radioactive cabergoline to five healthy volunteers, approximately 22% and 60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose was excreted unchanged in the urine. Nonrenal and renal clearances for cabergoline are about 3.2 L/min and 0.08 L/min, respectively. Urinary excretion in hyperprolactinemic patients was similar. - Special Populations - Renal Insufficiency - The pharmacokinetics of cabergoline were not altered in 12 patients with moderate-to-severe renal insufficiency as assessed by creatinine clearance. - Hepatic Insufficiency - In 12 patients with mild-to-moderate hepatic dysfunction (Child-Pugh score ≤ 10), no effect on mean cabergoline Cmax or area under the plasma concentration curve (AUC) was observed. However, patients with severe insufficiency (Child-Pugh score > 10) show a substantial increase in the mean cabergoline Cmax and AUC, and thus necessitate caution. - Elderly - Effect of age on the pharmacokinetics of cabergoline has not been studied. - Food-Drug Interaction - In 12 healthy adult volunteers, food did not alter cabergoline kinetics. ## Nonclinical Toxicology - Carcinogenicity studies were conducted in mice and rats with cabergoline given by gavage at doses up to 0.98 mg/kg/day and 0.32 mg/kg/day, respectively. These doses are 7 times and 4 times the maximum recommended human dose calculated on a body surface area basis using total mg/m2/week in rodents and mg/m2/week for a 50 kg human. - There was a slight increase in the incidence of cervical and uterine leiomyomas and uterine leiomyosarcomas in mice. In rats, there was a slight increase in malignant tumors of the cervix and uterus and interstitial cell adenomas. The occurrence of tumors in female rodents may be related to the prolonged suppression of prolactin secretion because prolactin is needed in rodents for the maintenance of the corpus luteum. In the absence of prolactin, the estrogen/progesterone ratio is increased, thereby increasing the risk for uterine tumors. In male rodents, the decrease in serum prolactin levels was associated with an increase in serum luteinizing hormone, which is thought to be a compensatory effect to maintain testicular steroid synthesis. Since these hormonal mechanisms are thought to be species-specific, the relevance of these tumors to humans is not known. - The mutagenic potential of cabergoline was evaluated and found to be negative in a battery of in vitro tests. These tests included the bacterial mutation (Ames) test with Salmonella typhimurium, the gene mutation assay with Schizosaccharomyces pombe P1 and V79 Chinese hamster cells, DNA damage and repair in Saccharomyces cerevisiae D4, and chromosomal aberrations in human lymphocytes. Cabergoline was also negative in the bone marrow micronucleus test in the mouse. - In female rats, a daily dose of 0.003 mg/kg for 2 weeks prior to mating and throughout the mating period inhibited conception. This dose represents approximately 1/28 the maximum recommended human dose calculated on a body surface area basis using total mg/m2/week in rats and mg/m2/week for a 50 kg human. # Clinical Studies - The prolactin-lowering efficacy of cabergoline was demonstrated in hyperprolactinemic women in two randomized, double-blind, comparative studies, one with placebo and the other with bromocriptine. In the placebo-controlled study (placebo n = 20; cabergoline n = 168), cabergoline produced a dose-related decrease in serum prolactin levels with prolactin normalized after 4 weeks of treatment in 29%, 76%, 74% and 95% of the patients receiving 0.125, 0.5, 0.75, and 1 mg twice weekly respectively. - In the 8 week, double-blind period of the comparative trial with bromocriptine (cabergoline n = 223; bromocriptine n = 236 in the intent-to-treat analysis), prolactin was normalized in 77% of the patients treated with cabergoline at 0.5 mg twice weekly compared with 59% of those treated with bromocriptine at 2.5 mg twice daily. Restoration of menses occurred in 77% of the women treated with cabergoline, compared with 70% of those treated with bromocriptine. Among patients with galactorrhea, this symptom disappeared in 73% of those treated with cabergoline compared with 56% of those treated with bromocriptine. # How Supplied - Cabergoline Tablets USP, 0.5 mg are available as white, oval-shaped, scored tablets, debossed Company Logo - “0.5” with a score on one side and “5420” on the other side containing 0.5 mg cabergoline, packaged in bottles of 8 tablets. - 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). ## Storage There is limited information regarding Cabergoline 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 Cabergoline in the drug label. # Precautions with Alcohol - Alcohol-Cabergoline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cabergoline® # Look-Alike Drug Names There is limited information regarding Cabergoline Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cabergoline 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 Cabergoline is a dopamine receptor agonist that is FDA approved for the {{{indicationType}}} of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas. Common adverse reactions include constipation, nausea, dizziness, headache and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dosage of cabergoline tablets for initiation of therapy is 0.25 mg twice a week. Dosage may be increased by 0.25 mg twice weekly up to a dosage of 1 mg twice a week according to the patient’s serum prolactin level. Before initiating treatment, cardiovascular evaluation should be performed and echocardiography should be considered to assess for valvular disease. - Dosage increases should not occur more rapidly than every 4 weeks, so that the physician can assess the patient’s response to each dosage level. If the patient does not respond adequately, and no additional benefit is observed with higher doses, the lowest dose that achieved maximal response should be used and other therapeutic approaches considered. Patients receiving long-term treatment with cabergoline should undergo periodic assessment of their cardiac status and echocardiography should be considered. - After a normal serum prolactin level has been maintained for 6 months, cabergoline may be discontinued, with periodic monitoring of the serum prolactin level to determine whether or when treatment with cabergoline should be reinstituted. The durability of efficacy beyond 24 months of therapy with cabergoline has not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cabergoline in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Cabergoline was given to patients not cured by prior therapy or as primary treatment. It was started at 0.5 milligrams (mg) twice weekly. The dose was increased, as needed, to 0.5 mg every 2 days (1.75 mg/week) - Dosing Information - Cabergoline 0.5 milligrams (mg) twice weekly for 4 months. - Dosing Information - Cabergoline 0.6 to 1 milligram as a single oral dose. - Dosing Information - Cabergoline at a maximum dose of 4 milligrams once daily either as monotherapy, or in association with levodopa/carbidopa. - Dosing Information - Cabergoline was initiated at 0.5 milligrams (mg)/day, with target doses ranging from 2 to 3 mg/day.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Cabergoline in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cabergoline in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cabergoline in pediatric patients. # Contraindications - Cabergoline tablets are contraindicated in patients with - Uncontrolled hypertension or known hypersensitivity to ergot derivatives. History of cardiac valvular disorders, as suggested by anatomical evidence of valvulopathy of any valve, determined by pre-treatment evaluation including echocardiographic demonstration of valve leaflet thickening, valve restriction, or mixed valve restriction-stenosis. History of pulmonary, pericardial, or retroperitoneal fibrotic disorders. - Uncontrolled hypertension or known hypersensitivity to ergot derivatives. - History of cardiac valvular disorders, as suggested by anatomical evidence of valvulopathy of any valve, determined by pre-treatment evaluation including echocardiographic demonstration of valve leaflet thickening, valve restriction, or mixed valve restriction-stenosis. - History of pulmonary, pericardial, or retroperitoneal fibrotic disorders. # Warnings ### Precautions - Pregnancy - Dopamine agonists in general should not be used in patients with pregnancy-induced hypertension, for example, preeclampsia, eclampsia, and post partum hypertension, unless the potential benefit is judged to outweigh the possible risk. - Fibrotic Complications - Cardiac Valvulopathy - All patients should undergo a cardiovascular evaluation, including echocardiogram to assess the potential presence of valvular disease. If valvular disease is detected, the patient should not be treated with cabergoline. Postmarketing cases of cardiac valvulopathy have been reported in patients receiving cabergoline. These cases have generally occurred during administration of high doses of cabergoline (> 2 mg/day) for the treatment of Parkinson’s disease. Cases of cardiac valvulopathy have also been reported in patients receiving lower doses of cabergoline for the treatment of hyperprolactinemic disorders. - A multi-country, retrospective cohort study using general practice records and record linkage systems in the UK, Italy and the Netherlands was conducted to assess the association between new use of dopamine agonists including cabergoline (n = 27,812) for Parkinson’s disease and hyperprolactinemia and cardiac valvular regurgitation (CVR), other fibroses, and other cardiopulmonary events over a maximum of 12 years of follow up. In this study, the use of cabergoline among persons with Parkinson's disease was associated with an increased risk of CVR when compared to non-ergot-derived dopamine agonists (DAs) and levodopa [Incidence Rate (IR) per 10,000 person years of 68.1 (95% confidence interval (CI): 37.2 to 115.3) for cabergoline vs. 10 (95% CI: 5.2 to 19.4) for non-ergot DAs and 11.3 (95% CI: 7.2 to 17) for levodopa]. In the study analysis confined to persons with dopamine agonist-treated hyperprolactinemia (n = 8,386), when compared to non-use (n = 15,147), persons exposed to cabergoline did not have an elevated risk of CVR. The findings with respect to the risk of CVR associated with cabergoline treatment for persons with Parkinson’s disease (increased risk) and those with hyperprolactinemia (no increased risk) are consistent with the findings in other published studies. - Physicians should use the lowest effective dose of cabergoline for the treatment of hyperprolactinemic disorders and should periodically reassess the need for continuing therapy with cabergoline. Following treatment initiation, clinical and diagnostic monitoring (for example, chest x-ray, CT scan and cardiac echocardiogram) should be conducted to assess the risk of cardiac valvulopathy. The recommended frequency of routine echocardiographic monitoring is every 6 to 12 months or as clinically indicated with the presence of signs and symptoms such as edema, new cardiac murmur, dyspnea, or congestive heart failure. - Cabergoline should be discontinued if an echocardiogram reveals new valvular regurgitation, valvular restriction or valve leaflet thickening. - Cabergoline should be used with caution in patients exposed to other medications associated with valvulopathy. - Extracardiac Fibrotic Reactions - Postmarketing cases of pleural, pericardial, and retroperitoneal fibrosis have been reported following administration of cabergoline. Some reports were in patients previously treated with other ergotinic dopamine agonists. Cabergoline should not be used in patients with a history of cardiac or extracardiac fibrotic disorders. - Fibrotic disorders can have an insidious onset and patients should be monitored for manifestations of progressive fibrosis. Therefore, during treatment, attention should be paid to the signs and symptoms of: Pleuro-pulmonary disease such as dyspnea, shortness of breath, persistent cough or chest pain. Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb edema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis. Cardiac failure: Cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur. - Pleuro-pulmonary disease such as dyspnea, shortness of breath, persistent cough or chest pain. - Renal insufficiency or ureteral/abdominal vascular obstruction that may occur with pain in the loin/flank and lower limb edema as well as any possible abdominal masses or tenderness that may indicate retroperitoneal fibrosis. - Cardiac failure: Cases of valvular and pericardial fibrosis have often manifested as cardiac failure. Therefore, valvular fibrosis (and constrictive pericarditis) should be excluded if such symptoms occur. - Clinical and diagnostic monitoring such as erythrocyte sedimentation rate, chest x-ray, serum creatinine measurements, and other investigations should be considered at baseline and as necessary while patients are treated with cabergoline. - Following diagnosis of pleural effusion or pulmonary fibrosis, the discontinuance of cabergoline was reported to result in improvement of signs and symptoms. - General - Initial doses higher than 1 mg may produce orthostatic hypotension. Care should be exercised when administering cabergoline with other medications known to lower blood pressure. - Postpartum Lactation Inhibition or Suppression - Cabergoline tablets are not indicated for the inhibition or suppression of physiologic lactation. Use of bromocriptine, another dopamine agonist for this purpose, has been associated with cases of hypertension, stroke, and seizures. - Hepatic Impairment - Since cabergoline is extensively metabolized by the liver, caution should be used, and careful monitoring exercised, when administering cabergoline to patients with hepatic impairment. - Psychiatric - Pathological gambling, increased libido, and hypersexuality have been reported in patients treated with dopamine agonists including cabergoline. This has been generally reversible upon reduction of the dose or treatment discontinuation. # Adverse Reactions ## Clinical Trials Experience - The safety of cabergoline tablets has been evaluated in more than 900 patients with hyperprolactinemic disorders. Most adverse events were mild or moderate in severity. - In a 4 week, double-blind, placebo-controlled study, treatment consisted of placebo or cabergoline at fixed doses of 0.125, 0.5, 0.75, or 1 mg twice weekly. Doses were halved during the first week. Since a possible dose-related effect was observed for nausea only, the four cabergoline treatment groups have been combined. The incidence of the most common adverse events during the placebo-controlled study is presented in the following table. - In the 8 week, double-blind period of the comparative trial with bromocriptine, cabergoline (at a dose of 0.5 mg twice weekly) was discontinued because of an adverse event in 4 of 221 patients (2%) while bromocriptine (at a dose of 2.5 mg two times a day) was discontinued in 14 of 231 patients (6%). The most common reasons for discontinuation from cabergoline were headache, nausea and vomiting (3, 2 and 2 patients respectively); the most common reasons for discontinuation from bromocriptine were nausea, vomiting, headache, and dizziness or vertigo (10, 3, 3, and 3 patients respectively). The incidence of the most common adverse events during the double-blind portion of the comparative trial with bromocriptine is presented in the following table. - Other adverse events that were reported at an incidence of < 1% in the overall clinical studies follow. Facial edema, influenza-like symptoms, malaise Hypotension, syncope, palpitations Dry mouth, flatulence, diarrhea, anorexia Weight loss, weight gain Somnolence, nervousness, paresthesia, insomnia, anxiety Nasal stuffiness, epistaxis Acne, pruritus Abnormal vision Dysmenorrhea, increased libido - The safety of cabergoline has been evaluated in approximately 1,200 patients with Parkinson’s disease in controlled and uncontrolled studies at dosages of up to 11.5 mg/day which greatly exceeds the maximum recommended dosage of cabergoline for hyperprolactinemic disorders. In addition to the adverse events that occurred in the patients with hyperprolactinemic disorders, the most common adverse events in patients with Parkinson’s disease were dyskinesia, hallucinations, confusion, and peripheral edema. Heart failure, pleural effusion, pulmonary fibrosis, and gastric or duodenal ulcer occurred rarely. One case of constrictive pericarditis has been reported. ## Postmarketing Experience - The following events have been reported in association with cabergoline: cardiac valvulopathy and extracardiac fibrotic reactions. - Other events have been reported in association with cabergoline: hypersexuality, increased libido, pathological gambling. In addition, cases of alopecia, aggression and psychotic disorder have been reported in patients taking cabergoline. Some of these reports have been in patients who have had prior adverse reactions to dopamine agonist products. # Drug Interactions - Cabergoline should not be administered concurrently with D2-antagonists, such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - Reproduction studies have been performed with cabergoline in mice, rats, and rabbits administered by gavage. - (Multiples of the maximum recommended human dose in this section are calculated on a body surface area basis using total mg/m2/week for animals and mg/m2/week for a 50 kg human.) - There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis. - A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in post-implantation embryofetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose). - In rats, doses higher than 0.003 mg/kg/day (approximately 1/28 the maximum recommended human dose) from 6 days before parturition and throughout the lactation period inhibited growth and caused death of offspring due to decreased milk secretion. - 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): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cabergoline in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cabergoline 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 cabergoline, 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. Use of cabergoline for the inhibition or suppression of physiologic lactation is not recommended (see PRECAUTIONS section). - The prolactin-lowering action of cabergoline suggests that it will interfere with lactation. Due to this interference with lactation, cabergoline should not be given to women postpartum who are breastfeeding or who are planning to breastfeed. ### Pediatric Use - Safety and effectiveness of cabergoline in pediatric patients have not been established. ### Geriatic Use - Clinical studies of cabergoline did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. 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, usually starting at the low end of the dosing range, 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 Cabergoline with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cabergoline with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Cabergoline in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Cabergoline in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cabergoline in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cabergoline in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Cabergoline in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Cabergoline in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. ### Management - Measures to support blood pressure should be taken if necessary. ## Chronic Overdose There is limited information regarding Chronic Overdose of Cabergoline in the drug label. # Pharmacology ## Mechanism of Action - The secretion of prolactin by the anterior pituitary is mainly under hypothalamic inhibitory control, likely exerted through release of dopamine by tuberoinfundibular neurons. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Results of in vitro studies demonstrate that cabergoline exerts a direct inhibitory effect on the secretion of prolactin by rat pituitary lactotrophs. Cabergoline decreased serum prolactin levels in reserpinized rats. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D1, α1- and α2-adrenergic, and 5-HT1- and 5-HT2-serotonin receptors. ## Structure - Cabergoline Tablets USP contain cabergoline, USP, a dopamine receptor agonist. The chemical name for cabergoline, USP is 1-[(6-Allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea and has the following structural formula: - Cabergoline, USP is a white powder soluble in ethyl alcohol, chloroform, and N, N-dimethylformamide (DMF); slightly soluble in 0.1N hydrochloric acid; very slightly soluble in n-hexane; and insoluble in water. - Each Cabergoline Tablet USP, for oral administration, contains 0.5 mg of cabergoline, USP and has the following inactive ingredients: anhydrous lactose and leucine. ## Pharmacodynamics - Dose response with inhibition of plasma prolactin, onset of maximal effect, and duration of effect has been documented following single cabergoline doses to healthy volunteers (0.05 to 1.5 mg) and hyperprolactinemic patients (0.3 to 1 mg). In volunteers, prolactin inhibition was evident at doses > 0.2 mg, while doses ≥ 0.5 mg caused maximal suppression in most subjects. Higher doses produce prolactin suppression in a greater proportion of subjects and with an earlier onset and longer duration of action. In 12 healthy volunteers, 0.5, 1, and 1.5 mg doses resulted in complete prolactin inhibition, with a maximum effect within 3 hours in 92% to 100% of subjects after the 1 and 1.5 mg doses compared with 50% of subjects after the 0.5 mg dose. - In hyperprolactinemic patients (N = 51), the maximal prolactin decrease after a 0.6 mg single dose of cabergoline was comparable to 2.5 mg bromocriptine; however, the duration of effect was markedly longer (14 days vs. 24 hours). The time to maximal effect was shorter for bromocriptine than cabergoline (6 hours vs. 48 hours). - In 72 healthy volunteers, single or multiple doses (up to 2 mg) of cabergoline resulted in selective inhibition of prolactin with no apparent effect on other anterior pituitary hormones (GH, FSH, LH, ACTH, and TSH) or cortisol. ## Pharmacokinetics - Absorption - Following single oral doses of 0.5 mg to 1.5 mg given to 12 healthy adult volunteers, mean peak plasma levels of 30 to 70 picograms (pg)/mL of cabergoline were observed within 2 to 3 hours. Over the 0.5 to 7 mg dose range, cabergoline plasma levels appeared to be dose-proportional in 12 healthy adult volunteers and nine adult parkinsonian patients. A repeat-dose study in 12 healthy volunteers suggests that steady-state levels following a once-weekly dosing schedule are expected to be two-fold to three-fold higher than after a single dose. The absolute bioavailability of cabergoline is unknown. A significant fraction of the administered dose undergoes a first-pass effect. The elimination half-life of cabergoline estimated from urinary data of 12 healthy subjects ranged between 63 to 69 hours. The prolonged prolactin-lowering effect of cabergoline may be related to its slow elimination and long half-life. - Distribution - In animals, based on total radioactivity, cabergoline (and/or its metabolites) has shown extensive tissue distribution. Radioactivity in the pituitary exceeded that in plasma by > 100 fold and was eliminated with a half-life of approximately 60 hours. This finding is consistent with the long-lasting prolactin-lowering effect of the drug. Whole body autoradiography studies in pregnant rats showed no fetal uptake but high levels in the uterine wall. Significant radioactivity (parent plus metabolites) detected in the milk of lactating rats suggests a potential for exposure to nursing infants. The drug is extensively distributed throughout the body. Cabergoline is moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. Concomitant dosing of highly protein-bound drugs is unlikely to affect its disposition. - Metabolism - In both animals and humans, cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond or the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. Cabergoline does not cause enzyme induction and/or inhibition in the rat. Hydrolysis of the acylurea or urea moiety abolishes the prolactin-lowering effect of cabergoline, and major metabolites identified thus far do not contribute to the therapeutic effect. - Excretion - After oral dosing of radioactive cabergoline to five healthy volunteers, approximately 22% and 60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose was excreted unchanged in the urine. Nonrenal and renal clearances for cabergoline are about 3.2 L/min and 0.08 L/min, respectively. Urinary excretion in hyperprolactinemic patients was similar. - Special Populations - Renal Insufficiency - The pharmacokinetics of cabergoline were not altered in 12 patients with moderate-to-severe renal insufficiency as assessed by creatinine clearance. - Hepatic Insufficiency - In 12 patients with mild-to-moderate hepatic dysfunction (Child-Pugh score ≤ 10), no effect on mean cabergoline Cmax or area under the plasma concentration curve (AUC) was observed. However, patients with severe insufficiency (Child-Pugh score > 10) show a substantial increase in the mean cabergoline Cmax and AUC, and thus necessitate caution. - Elderly - Effect of age on the pharmacokinetics of cabergoline has not been studied. - Food-Drug Interaction - In 12 healthy adult volunteers, food did not alter cabergoline kinetics. ## Nonclinical Toxicology - Carcinogenicity studies were conducted in mice and rats with cabergoline given by gavage at doses up to 0.98 mg/kg/day and 0.32 mg/kg/day, respectively. These doses are 7 times and 4 times the maximum recommended human dose calculated on a body surface area basis using total mg/m2/week in rodents and mg/m2/week for a 50 kg human. - There was a slight increase in the incidence of cervical and uterine leiomyomas and uterine leiomyosarcomas in mice. In rats, there was a slight increase in malignant tumors of the cervix and uterus and interstitial cell adenomas. The occurrence of tumors in female rodents may be related to the prolonged suppression of prolactin secretion because prolactin is needed in rodents for the maintenance of the corpus luteum. In the absence of prolactin, the estrogen/progesterone ratio is increased, thereby increasing the risk for uterine tumors. In male rodents, the decrease in serum prolactin levels was associated with an increase in serum luteinizing hormone, which is thought to be a compensatory effect to maintain testicular steroid synthesis. Since these hormonal mechanisms are thought to be species-specific, the relevance of these tumors to humans is not known. - The mutagenic potential of cabergoline was evaluated and found to be negative in a battery of in vitro tests. These tests included the bacterial mutation (Ames) test with Salmonella typhimurium, the gene mutation assay with Schizosaccharomyces pombe P1 and V79 Chinese hamster cells, DNA damage and repair in Saccharomyces cerevisiae D4, and chromosomal aberrations in human lymphocytes. Cabergoline was also negative in the bone marrow micronucleus test in the mouse. - In female rats, a daily dose of 0.003 mg/kg for 2 weeks prior to mating and throughout the mating period inhibited conception. This dose represents approximately 1/28 the maximum recommended human dose calculated on a body surface area basis using total mg/m2/week in rats and mg/m2/week for a 50 kg human. # Clinical Studies - The prolactin-lowering efficacy of cabergoline was demonstrated in hyperprolactinemic women in two randomized, double-blind, comparative studies, one with placebo and the other with bromocriptine. In the placebo-controlled study (placebo n = 20; cabergoline n = 168), cabergoline produced a dose-related decrease in serum prolactin levels with prolactin normalized after 4 weeks of treatment in 29%, 76%, 74% and 95% of the patients receiving 0.125, 0.5, 0.75, and 1 mg twice weekly respectively. - In the 8 week, double-blind period of the comparative trial with bromocriptine (cabergoline n = 223; bromocriptine n = 236 in the intent-to-treat analysis), prolactin was normalized in 77% of the patients treated with cabergoline at 0.5 mg twice weekly compared with 59% of those treated with bromocriptine at 2.5 mg twice daily. Restoration of menses occurred in 77% of the women treated with cabergoline, compared with 70% of those treated with bromocriptine. Among patients with galactorrhea, this symptom disappeared in 73% of those treated with cabergoline compared with 56% of those treated with bromocriptine. # How Supplied - Cabergoline Tablets USP, 0.5 mg are available as white, oval-shaped, scored tablets, debossed Company Logo - “0.5” with a score on one side and “5420” on the other side containing 0.5 mg cabergoline, packaged in bottles of 8 tablets. - 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). ## Storage There is limited information regarding Cabergoline 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 Cabergoline in the drug label. # Precautions with Alcohol - Alcohol-Cabergoline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Cabergoline®[2] # Look-Alike Drug Names There is limited information regarding Cabergoline Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cabergoline
0eaf35f8d81994da3c59ff5de76307b544be40e2	wikidoc	Calcifediol	Calcifediol # Overview Calcifediol (INN), also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D (abbreviated 25(OH)D), is a prehormone that is produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme cholecalciferol 25-hydroxylase which was isolated by Michael F. Holick. Physicians worldwide measure this metabolite to determine a patient's vitamin D status. Calcifediol is then converted in the kidneys (by the enzyme 25(OH)D-1α-hydroxylase) into calcitriol (1,25-(OH)2D3), a secosteroid hormone that is the active form of vitamin D. It can also be converted into 24-hydroxycalcidiol in the kidneys via 24-hydroxylation. # Blood test In medicine, a 25-hydroxy vitamin D (calcidiol) blood test is used to determine how much vitamin D is in the body. The blood concentration of calcidiol is considered the best indicator of vitamin D status. This test can be used to diagnose vitamin D deficiency, and it is indicated in patients with high risk for vitamin D deficiency and when the results of the test would be used as supporting evidence for beginning aggressive therapies. Patients with osteoporosis, chronic kidney disease, malabsorption, obesity, and some other infections may be high risk and thus have greater indication for this test. Although vitamin D deficiency is common in some populations including those living at higher latitudes or with limited sun exposure, the 25(OH)D test is not indicated for entire populations. Physicians may advise low risk patients to take over-the-counter vitamin D in place of having screening. It is the most sensitive measure, though experts have called for improved standardization and reproducibility across different laboratories. According to MedlinePlus, the normal range of calcidiol is 30.0 to 74.0 ng/mL. The normal range varies widely depending on several factors, including age and geographic location. A broad reference range of 20–150 nmol/L (8-60 ng/ml) has also been suggested, while other studies have defined levels below 80 nmol/L (32 ng/ml) as indicative of vitamin D deficiency. US labs generally report 25(OH)D levels as ng/mL. Other countries often use nmol/L. Multiply ng/mL by 2.5 to convert to nmol/L. ## Clinical significance Increasing calcidiol levels are associated with increasing fractional absorption of calcium from the gut up to levels of 80 nmol/L (32 ng/mL). A study by Cedric F. Garland and Frank C. Garland of the University of California, San Diego analyzed the blood from 25,000 volunteers from Washington County, Maryland, finding that those with the highest levels of calcifediol had a risk of colon cancer that was one-fifth of typical rates. However, randomized controlled trials failed to find a significant correlation between vitamin D supplementation and the risk of colon cancer.	Calcifediol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Calcifediol (INN), also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D (abbreviated 25(OH)D),[1] is a prehormone that is produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme cholecalciferol 25-hydroxylase which was isolated by Michael F. Holick. Physicians worldwide measure this metabolite to determine a patient's vitamin D status.[2] Calcifediol is then converted in the kidneys (by the enzyme 25(OH)D-1α-hydroxylase) into calcitriol (1,25-(OH)2D3), a secosteroid hormone that is the active form of vitamin D. It can also be converted into 24-hydroxycalcidiol in the kidneys via 24-hydroxylation.[3][4] # Blood test In medicine, a 25-hydroxy vitamin D (calcidiol) blood test is used to determine how much vitamin D is in the body.[5] The blood concentration of calcidiol is considered the best indicator of vitamin D status.[6] This test can be used to diagnose vitamin D deficiency, and it is indicated in patients with high risk for vitamin D deficiency and when the results of the test would be used as supporting evidence for beginning aggressive therapies.[7] Patients with osteoporosis, chronic kidney disease, malabsorption, obesity, and some other infections may be high risk and thus have greater indication for this test.[7] Although vitamin D deficiency is common in some populations including those living at higher latitudes or with limited sun exposure, the 25(OH)D test is not indicated for entire populations.[7] Physicians may advise low risk patients to take over-the-counter vitamin D in place of having screening.[7] It is the most sensitive measure,[8] though experts have called for improved standardization and reproducibility across different laboratories.[6] According to MedlinePlus, the normal range of calcidiol is 30.0 to 74.0 ng/mL. The normal range varies widely depending on several factors, including age and geographic location. A broad reference range of 20–150 nmol/L (8-60 ng/ml) has also been suggested,[9] while other studies have defined levels below 80 nmol/L (32 ng/ml) as indicative of vitamin D deficiency.[10] US labs generally report 25(OH)D levels as ng/mL. Other countries often use nmol/L. Multiply ng/mL by 2.5 to convert to nmol/L. ## Clinical significance Increasing calcidiol levels are associated with increasing fractional absorption of calcium from the gut up to levels of 80 nmol/L (32 ng/mL). A study by Cedric F. Garland and Frank C. Garland of the University of California, San Diego analyzed the blood from 25,000 volunteers from Washington County, Maryland, finding that those with the highest levels of calcifediol had a risk of colon cancer that was one-fifth of typical rates. However, randomized controlled trials failed to find a significant correlation between vitamin D supplementation and the risk of colon cancer.[11]	https://www.wikidoc.org/index.php/Calcifediol
465f112bc09912f91f7054e0b6b5cefc0c154063	wikidoc	Epithelioma	Epithelioma Synonyms and keywords: Pilomatrixoma; Calcifying Epithelioma of Malherbe; Epithelioma cuniculatum; Carcinoma cuniculatum; Superficial epithelioma # Overview Epithelioma is an abnormal growth of the epithelium, which is the layer of tissue that covers the surfaces of organs and other structures of the body. # Historical Perspective - Epithelioma cuniculatum was first discovered by Aird et al. in 1954. - Epithelioma cuniculatum is derived from the words epithelioma, meaning "tumor of the epithelium," and cuniculate, referring to crypt-like spaces seen on histology that resemble rabbit burrows. # Classification - The term epithelioma is usually considered for skin tumors originating from the epithelial origin also known as carcinoma cutis. However, epithelial tumors can arise from any epithelial lining of the organs including ovarian, uterine, glands, prostate, thyroid, lacrimal gland among others - Epithelioma may be classified according to nature of tumor into 2 sub-types: Benign growths Malignant carcinomas Basal cell carcinoma Squamous cell carcinoma Mixed or squamo-basal - Benign growths - Malignant carcinomas Basal cell carcinoma Squamous cell carcinoma Mixed or squamo-basal - Basal cell carcinoma - Squamous cell carcinoma - Mixed or squamo-basal - Basal and the squamous cell carcinomas are the most common types of epithelioma's # Pathophysiology - On gross pathology, bulky exophytic mass are characteristic findings of epithelioma. However there is a variance in the presentation of epithelioma - Clinical picture can range anywhere from superficial to deep, simple papillary to nodular appearance, fungoid, ulcerated, or cauliflower shaped - On microscopic histopathological analysis, endophytic and exophytic growth pattern, histiocytes, eosinophils, plasma cells, hyperchromasia, and mitoses are characteristic findings of epithelioma. # Causes - Epithelioma of the skin may be caused by; trauma Chronic irritation HPV infection Prolonged sun exposure Occupational exposure to tar and certain oils Pre-cancerous dermatosus - these are the benign skin lesions that develop as a result of trauma or any other condition that may serve as a base for development of epithelial skin cancers. examples include; Senile Keratosis Leukoplakia Radiation dermatitis Xeroderma Cutaneous horns Old scars Chronic ulceration Warts Sebaceous cysts Pigmented nevi Psoriatic or eczematous lesions SLE skin lesions Lupus vulgaris - trauma - Chronic irritation - HPV infection - Prolonged sun exposure - Occupational exposure to tar and certain oils - Pre-cancerous dermatosus - these are the benign skin lesions that develop as a result of trauma or any other condition that may serve as a base for development of epithelial skin cancers. examples include; Senile Keratosis Leukoplakia Radiation dermatitis Xeroderma Cutaneous horns Old scars Chronic ulceration Warts Sebaceous cysts Pigmented nevi Psoriatic or eczematous lesions SLE skin lesions Lupus vulgaris - Senile Keratosis - Leukoplakia - Radiation dermatitis - Xeroderma - Cutaneous horns - Old scars - Chronic ulceration - Warts - Sebaceous cysts - Pigmented nevi - Psoriatic or eczematous lesions - SLE skin lesions - Lupus vulgaris # Differentiating Epithelioma from other Diseases - Epithelioma must be differentiated from other diseases that cause skin masses, such as: - Seborrheic keratosis with sebaceous differentiation - Sebaceous hyperplasia - Sebaceous adenoma - Sebaceous carcinoma # Epidemiology and Demographics ## Age - Epithelioma is more commonly seen in older patients more than 50 years of age. Incidence in age 55 to 75 is 100 times higher as compared to 20 years old. ## Gender - Males are more commonly affected with epithelioma as compared to females. ## Race - Epithelioma is seen more commonly in Caucasians. - Not common in dark skinned people # Risk Factors - Common risk factors in the development of epithelioma are trauma, chronic irritation, and HPV infection, prolonged sun exposure as well as occupational exposure to tar and certain oils. An additional risk factor is the presence of benign skin conditions called pre-cancerous dermatosus which include warts,dermatitis, leukoplakia, eczematous or psoriatic liesions, sebborhic keratosis, SLE skin lesions, nevi and cutaneous horns. # Natural History, Complications and Prognosis ## Prognosis - The prognosis of the epithelioma is variable, depending on the type, location, extent and stage at the time of diagnosis and hence treatment. - However, most of the epitheliomas can be treated easily and the prognosis is good # Diagnosis ## Symptoms - Epithelioma of the skin can present in any form, usually easy to diagnose. Some of the presentations may include: New mole/growing mole/mole changing color New or growing warty lesion Painless swelling Indurated or ulcerated lesion Chronic scar that starts bleeding or changing - New mole/growing mole/mole changing color - New or growing warty lesion - Painless swelling - Indurated or ulcerated lesion - Chronic scar that starts bleeding or changing - Epithelial tumors of the organs can present in any way ranging from swelling or mass to symptoms related to involved organ system ## Physical Examination - Physical examination for epithelioma of the skin may be remarkable for: Non tender swelling Hard, waxy nodules with pearly borders Ulceration or Induration - Non tender swelling - Hard, waxy nodules with pearly borders - Ulceration or Induration ## Laboratory Findings - There are no specific laboratory findings associated with epithelioma. However tests can be performed to rule out other causes of skin lesions like syphilis, lupus vulgaris, allergies etc. ## Other Diagnostic Studies - Any suspicious skin lesion should be biopsied. Histopathology is the most accurate way of diagnosing a skin condition or identifying or ruling out a malignancy of the skin. # Treatment There is no single method of treatment since treatment procedure and extent depends upon the location and extent as well as the stage of the tumor along with the age and the sex of the patient. Some common treatment methods include - Surgical excision - Irraditation - Electrocauterisation - Combination Therapy- Surgery plus electrocauteristaion plus irradiation Involves curreting the lesion under local anesthesia followed by cauterization of the base by the chemical method(zinc chloride or nitrate) followed by irradiation - Involves curreting the lesion under local anesthesia followed by cauterization of the base by the chemical method(zinc chloride or nitrate) followed by irradiation - Combination therapy - Surgery plus radiation (usually used in case of advanced tumors with metastasis or infilltration) Some other treatment options include: - Cryosurgery - Podophyllin - Treatment with tissue extract - Chemosurgery - usually for recurrent basal cell epitheliomas	Epithelioma Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anila Hussain, MD [2]Ammu Susheela, M.D. [3] Synonyms and keywords: Pilomatrixoma; Calcifying Epithelioma of Malherbe; Epithelioma cuniculatum; Carcinoma cuniculatum; Superficial epithelioma # Overview Epithelioma is an abnormal growth of the epithelium, which is the layer of tissue that covers the surfaces of organs and other structures of the body. # Historical Perspective - Epithelioma cuniculatum was first discovered by Aird et al. in 1954.[1] - Epithelioma cuniculatum is derived from the words epithelioma, meaning "tumor of the epithelium," and cuniculate, referring to crypt-like spaces seen on histology that resemble rabbit burrows. # Classification - The term epithelioma is usually considered for skin tumors originating from the epithelial origin also known as carcinoma cutis[2]. However, epithelial tumors can arise from any epithelial lining of the organs including ovarian, uterine, glands, prostate, thyroid, lacrimal gland among others - Epithelioma may be classified according to nature of tumor into 2 sub-types: Benign growths Malignant carcinomas Basal cell carcinoma Squamous cell carcinoma Mixed or squamo-basal - Benign growths - Malignant carcinomas Basal cell carcinoma Squamous cell carcinoma Mixed or squamo-basal - Basal cell carcinoma - Squamous cell carcinoma - Mixed or squamo-basal - Basal and the squamous cell carcinomas are the most common types of epithelioma's # Pathophysiology - On gross pathology, bulky exophytic mass are characteristic findings of epithelioma. However there is a variance in the presentation of epithelioma - Clinical picture can range anywhere from superficial to deep, simple papillary to nodular appearance, fungoid, ulcerated, or cauliflower shaped - On microscopic histopathological analysis, endophytic and exophytic growth pattern, histiocytes, eosinophils, plasma cells, hyperchromasia, and mitoses are characteristic findings of epithelioma. # Causes - Epithelioma of the skin may be caused by[3]; trauma Chronic irritation HPV infection Prolonged sun exposure Occupational exposure to tar[4] and certain oils Pre-cancerous dermatosus - these are the benign skin lesions that develop as a result of trauma or any other condition that may serve as a base for development of epithelial skin cancers. examples include; Senile Keratosis Leukoplakia Radiation dermatitis Xeroderma Cutaneous horns Old scars Chronic ulceration Warts Sebaceous cysts Pigmented nevi Psoriatic or eczematous lesions SLE skin lesions Lupus vulgaris - trauma - Chronic irritation - HPV infection - Prolonged sun exposure - Occupational exposure to tar[4] and certain oils - Pre-cancerous dermatosus - these are the benign skin lesions that develop as a result of trauma or any other condition that may serve as a base for development of epithelial skin cancers. examples include; Senile Keratosis Leukoplakia Radiation dermatitis Xeroderma Cutaneous horns Old scars Chronic ulceration Warts Sebaceous cysts Pigmented nevi Psoriatic or eczematous lesions SLE skin lesions Lupus vulgaris - Senile Keratosis - Leukoplakia - Radiation dermatitis - Xeroderma - Cutaneous horns - Old scars - Chronic ulceration - Warts - Sebaceous cysts - Pigmented nevi - Psoriatic or eczematous lesions - SLE skin lesions - Lupus vulgaris - # Differentiating Epithelioma from other Diseases - Epithelioma must be differentiated from other diseases that cause skin masses, such as: - Seborrheic keratosis with sebaceous differentiation - Sebaceous hyperplasia - Sebaceous adenoma - Sebaceous carcinoma # Epidemiology and Demographics[5] ## Age - Epithelioma is more commonly seen in older patients more than 50 years of age. Incidence in age 55 to 75 is 100 times higher as compared to 20 years old. ## Gender - Males are more commonly affected with epithelioma as compared to females. ## Race - Epithelioma is seen more commonly in Caucasians. - Not common in dark skinned people # Risk Factors - Common risk factors in the development of epithelioma are trauma, chronic irritation, and HPV infection, prolonged sun exposure as well as occupational exposure to tar[4] and certain oils. An additional risk factor is the presence of benign skin conditions called pre-cancerous dermatosus which include warts,dermatitis, leukoplakia, eczematous or psoriatic liesions, sebborhic keratosis, SLE skin lesions, nevi and cutaneous horns. # Natural History, Complications and Prognosis ## Prognosis - The prognosis of the epithelioma is variable, depending on the type, location, extent and stage at the time of diagnosis and hence treatment. - However, most of the epitheliomas can be treated easily and the prognosis is good # Diagnosis ## Symptoms - Epithelioma of the skin can present in any form, usually easy to diagnose. Some of the presentations may include: New mole/growing mole/mole changing color New or growing warty lesion Painless swelling Indurated or ulcerated lesion Chronic scar that starts bleeding or changing - New mole/growing mole/mole changing color - New or growing warty lesion - Painless swelling - Indurated or ulcerated lesion - Chronic scar that starts bleeding or changing - Epithelial tumors of the organs can present in any way ranging from swelling or mass to symptoms related to involved organ system ## Physical Examination - Physical examination for epithelioma of the skin may be remarkable for: Non tender swelling Hard, waxy nodules with pearly borders Ulceration or Induration - Non tender swelling - Hard, waxy nodules with pearly borders - Ulceration or Induration ## Laboratory Findings - There are no specific laboratory findings associated with epithelioma. However tests can be performed to rule out other causes of skin lesions like syphilis, lupus vulgaris, allergies etc. ## Other Diagnostic Studies - Any suspicious skin lesion should be biopsied. Histopathology is the most accurate way of diagnosing a skin condition or identifying or ruling out a malignancy of the skin. # Treatment There is no single method of treatment since treatment procedure and extent depends upon the location and extent as well as the stage of the tumor along with the age and the sex of the patient. Some common treatment methods include[6][7] - Surgical excision - Irraditation - Electrocauterisation - Combination Therapy- Surgery plus electrocauteristaion plus irradiation Involves curreting the lesion under local anesthesia followed by cauterization of the base by the chemical method(zinc chloride or nitrate) followed by irradiation - Involves curreting the lesion under local anesthesia followed by cauterization of the base by the chemical method(zinc chloride or nitrate) followed by irradiation - Combination therapy - Surgery plus radiation (usually used in case of advanced tumors with metastasis or infilltration) Some other treatment options include: - Cryosurgery - Podophyllin - Treatment with tissue extract - Chemosurgery - usually for recurrent basal cell epitheliomas -	https://www.wikidoc.org/index.php/Calcifying_Epithelioma_of_Malherbe
23325ab107837785e4933a1101ed9c8ecd2990cd	wikidoc	Calcineurin	Calcineurin Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of the T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which include ciclosporin, voclosporin, pimecrolimus and tacrolimus. # Structure Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca2+-binding regulatory subunit, calcineurin B. There are three isozymes of the catalytic subunit, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two isoforms of the regulatory, also encoded by separate genes (PPP3R1, PPP3R2). # Mechanism of action When an antigen-presenting cell interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium, which activates calcineurin by binding a regulatory subunit and activating calmodulin binding. Calcineurin induces transcription factors (NFATs) that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. In this way, it governs the action of cytotoxic lymphocytes. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly. # Clinical relevance ## Rheumatic diseases Calcineurin inhibitors are prescribed for adult rheumatoid arthritis (RA) as a single drug or in combination with methotrexate. The microemulsion formulation is approved by the U.S. Food and Drug Administration for treatment of severely active RA. It is also prescribed for: psoriatic arthritis, psoriasis, acute ocular Behçet’s disease, juvenile idiopathic arthritis, adult and juvenile polymyositis and dermatomyositis, adult and juvenile systemic lupus erythematosus, adult lupus membranous nephritis, systemic sclerosis, aplastic anemia, steroid-resistant nephrotic syndrome, atopic dermatitis, severe corticosteroid-dependent asthma, severe ulcerative colitis, pemphigus vulgaris, myasthenia gravis, and dry eye disease, with or without Sjögren's syndrome (administered as ophthalmic emulsion). ## Schizophrenia Calcineurin is linked to receptors for several brain chemicals including glutamate, dopamine and GABA. An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans with schizophrenia: impairment in working memory, attention deficits, aberrant social behavior, and several other abnormalities characteristic of schizophrenia. ## Diabetes Calcineurin along with NFAT, may improve the function of diabetics' pancreatic beta cells. Thus tacrolimus contributes to the frequent development of new diabetes following renal transplantation. Calcineurin/NFAT signaling is required for perinatal lung maturation and function. # Interactions Calcineurin has been shown to interact with DSCR1 and AKAP5.	Calcineurin Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase).[2] It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of the T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which include ciclosporin, voclosporin, pimecrolimus and tacrolimus. # Structure Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca2+-binding regulatory subunit, calcineurin B. There are three isozymes of the catalytic subunit, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two isoforms of the regulatory, also encoded by separate genes (PPP3R1, PPP3R2). # Mechanism of action When an antigen-presenting cell interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium, which activates calcineurin by binding a regulatory subunit and activating calmodulin binding.[3] Calcineurin induces transcription factors (NFATs) that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. In this way, it governs the action of cytotoxic lymphocytes. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly. # Clinical relevance ## Rheumatic diseases Calcineurin inhibitors are prescribed for adult rheumatoid arthritis (RA) as a single drug or in combination with methotrexate. The microemulsion formulation is approved by the U.S. Food and Drug Administration for treatment of severely active RA. It is also prescribed for: psoriatic arthritis, psoriasis, acute ocular Behçet’s disease, juvenile idiopathic arthritis, adult and juvenile polymyositis and dermatomyositis, adult and juvenile systemic lupus erythematosus, adult lupus membranous nephritis, systemic sclerosis, aplastic anemia, steroid-resistant nephrotic syndrome, atopic dermatitis, severe corticosteroid-dependent asthma, severe ulcerative colitis, pemphigus vulgaris, myasthenia gravis, and dry eye disease, with or without Sjögren's syndrome (administered as ophthalmic emulsion).[4] ## Schizophrenia Calcineurin is linked to receptors for several brain chemicals including glutamate, dopamine and GABA.[5] An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans with schizophrenia: impairment in working memory, attention deficits, aberrant social behavior, and several other abnormalities characteristic of schizophrenia.[6] ## Diabetes Calcineurin along with NFAT, may improve the function of diabetics' pancreatic beta cells.[7][8] Thus tacrolimus contributes to the frequent development of new diabetes following renal transplantation.[9] Calcineurin/NFAT signaling is required for perinatal lung maturation and function.[10] # Interactions Calcineurin has been shown to interact with DSCR1[11] and AKAP5.[12]	https://www.wikidoc.org/index.php/Calcineurin
283e8bee7ce8f294fdfc7c9fa2b838f44b352eac	wikidoc	Perfect gas	Perfect gas By definition, a perfect gas is one in which intermolecular forces are neglected. So, along with the assumptions of an ideal gas, the following assumptions are added: - Neglected intermolecular forces By neglecting these forces, the equation of state for a perfect gas can be simply derived from kinetic theory or statistical mechanics. This type of assumption is useful for making calculations very simple and easy to do. With this assumption we can apply the Ideal gas law without restriction and neglect many complications that may arise from the Van der Waals forces. Along with the definition of a perfect gas, there are also two more simplifications that can be made although various textbooks either omit or combine the following simplifications into a general "perfect gas" definition. For the sake of clarity, these simplifications are defined separately. # Thermally perfect - The gas is in thermodynamic equilibrium - Not chemically reacting - Internal energy, enthalpy, and specific heat are functions of temperature only. e = e(T) h = h(T) de = C_vdT dh = C_pdT This type of approximation is useful for modeling, for example, an axial compressor where temperature fluctuations are usually not large enough to cause any significant deviations from the thermally perfect gas model. Heat capacity is still allowed to vary, though only with temperature, and molecules are not permitted to dissociate. # Calorically perfect Finally, the most restricted gas model is one where all the above assumptions apply and we also apply: - Constant Specific Heats e = C_vT h = C_pT Although this may be the most restrictive model, it still may be accurate enough to make reasonable calculations. For example, if a model of one compression stage of the axial compressor mentioned in the previous example was made (one with variable C_p, and one with constant C_p) to compare the two simplifications, the deviation may be found at a small enough order of magnitude that other factors that come into play in this compression would have a greater impact on the final result than whether or not C_p was held constant (compressor tip-clearance, boundary layer/frictional losses, manufacturing impurities, etc).	Perfect gas By definition, a perfect gas is one in which intermolecular forces are neglected. So, along with the assumptions of an ideal gas, the following assumptions are added: - Neglected intermolecular forces By neglecting these forces, the equation of state for a perfect gas can be simply derived from kinetic theory or statistical mechanics. This type of assumption is useful for making calculations very simple and easy to do. With this assumption we can apply the Ideal gas law without restriction and neglect many complications that may arise from the Van der Waals forces. Along with the definition of a perfect gas, there are also two more simplifications that can be made although various textbooks either omit or combine the following simplifications into a general "perfect gas" definition. For the sake of clarity, these simplifications are defined separately. ### Thermally perfect - The gas is in thermodynamic equilibrium - Not chemically reacting - Internal energy, enthalpy, and specific heat are functions of temperature only. <math>e = e(T)</math> <math>h = h(T)</math> <math>de = C_vdT</math> <math>dh = C_pdT</math> This type of approximation is useful for modeling, for example, an axial compressor where temperature fluctuations are usually not large enough to cause any significant deviations from the thermally perfect gas model. Heat capacity is still allowed to vary, though only with temperature, and molecules are not permitted to dissociate. ### Calorically perfect Finally, the most restricted gas model is one where all the above assumptions apply and we also apply: - Constant Specific Heats <math>e = C_vT</math> <math>h = C_pT</math> Although this may be the most restrictive model, it still may be accurate enough to make reasonable calculations. For example, if a model of one compression stage of the axial compressor mentioned in the previous example was made (one with variable <math>C_p</math>, and one with constant <math>C_p</math>) to compare the two simplifications, the deviation may be found at a small enough order of magnitude that other factors that come into play in this compression would have a greater impact on the final result than whether or not <math>C_p</math> was held constant (compressor tip-clearance, boundary layer/frictional losses, manufacturing impurities, etc).	https://www.wikidoc.org/index.php/Calorically_perfect_gas
d4dd10ba5fce23f7b98649af6b235bdd35246e2d	wikidoc	Calorimeter	Calorimeter A calorimeter is a device used for calorimetry, the science of measuring the heat of chemical reactions or physical changes as well as heat capacity. The word calorimeter is derived from the Latin word calor, meaning heat. Differential scanning calorimeters, isothermal microcalorimeters, titration calorimeters and accelerated rate calorimeters are among the most common types. A simple calorimeter just consists of a thermometer attached to an insulated container. To find the enthalpy change per mole of a substance X in a reaction between two liquids X and Y, they are added to the calorimeter and the initial and final (after the reaction has finished) temperatures are noted. Multiplying the temperature change by the mass and specific heat capacities of the liquids gives a value for the energy given off during the reaction (assuming the reaction was exothermic.). Dividing the energy change by how many moles of X were present gives its enthalpy change of reaction. This method is used primarily in academic teaching as it describes the theory of calorimetry. It doesn’t however account for the heat loss through the container or the heat capacity of the thermometer and container itself. In addition, the object placed inside the calorimeter show that the objects transferred their heat to the calorimeter and into the liquid, and the heat absorbed by the calorimeter and the liquid is equal to the heat given off by the metals. # Types ## Reaction calorimeters A reaction calorimeter is a calorimeter in which a chemical reaction is initiated within a closed insulated container. Reaction heats are measured and the total heat is obtained by integrating heatflow versus time. This is the standard used in industry to measure heats since industrial processes are engineered to run at constant temperatures. Reaction calorimetry can also be used to determine maximum heat release rate for chemical process engineering and for tracking the global kinetics of reactions. There are three common methods for measuring heat in reaction calorimeter: Heat flow calorimetry The cooling/heating jacket controls the temperature of the process. Heat is measured by monitoring the temperature difference between heat transfer fluid and the process fluid as follows: Q = UA(T-t) where Heat flow calorimetry allows the user to measure heat whilst the process temperature remains under control. It is however a difficult technique to use and not particularly accurate. The value of U has to be predetermined by careful experimentation and any change in product composition, liquid level, process temperature, agitation rate or viscosity will upset the calibration. A variation of the 'heat flow' technique is called 'power compensation' calorimetry. This method uses a cooling jacket operating at constant flow and temperature. The process temperature is regulated by adjusting the power of the electrical heater. When the experiment is started, the electrical heat and the cooling power (of the cooling jacket) are in balance. As the process heat load changes, the electrical power is varied in order to maintain the desired process temperature. The heat liberated or absorbed by the process is determined from the difference between the initial electrical power and the demand for electrical power at the time of measurement. The power compensation method is easier to set up than heat flow calorimetry but it suffers from the similar limitations since any change in product composition, liquid level, process temperature, agitation rate or viscosity will upset the calibration. The presence of an electrical heating element is also undesirable for process operations. Heat balance calorimetry The cooling/heating jacket controls the temperature of the process. Heat is measured by monitoring the heat gained or lost by the heat transfer fluid as follows: Q = m_s C_{ps}(T_i - T_o) where Heat balance calorimetry is, in principle, the ideal method of measuring heat since the heat entering and leaving the system through the heating/cooling jacket is measured from the heat transfer fluid (which has known properties). This eliminates most of the calibration problems encountered by heat flow and power compensation calorimetry. Unfortunately, the method does not work well in traditional batch vessels since the process heat signal is obscured by large heat shifts in the cooling/heating jacket. A recent development in calorimetry however is that of constant flux cooling/heating jackets. These use variable geometry cooling jackets and can operate with cooling jackets at substantially constant temperature. These reaction calorimeters tend to be much simpler to use and are much more tolerant of changes in the process conditions (which would affect calibration in heat flow or power compensation calorimeters). ### Bomb calorimeters A bomb calorimeter is a type of constant-volume calorimeter used in measuring the heat of combustion of a particular reaction. Bomb calorimeters have to withstand the large pressure and force of the calorimeter as the reaction is being measured. Electrical energy is used to ignite the fuel, as the fuel is burning, it will heat up the surrounding air, which expands and escapes through a tube that leads the air out of the calorimeter. When the air is escaping through the copper tube it will also heat up the water outside the tube. The temperature of the water allows for calculating calorie content of the fuel. In more recent calorimeter designs, the whole bomb, pressurized with excess pure oxygen (typically at 20atm) and containing a known mass of fuel, is submerged under a known volume of water before the charge is (again electrically) ignited. The bomb, with fuel and oxygen, form a closed system - no air escapes during the reaction. The energy released by the combustion raises the temperature of the steel bomb, its contents, and the surrounding water jacket. The temperature change in the water is then accurately measured. This temperature rise, along with a bomb factor (which is dependent on the heat capacity of the metal bomb parts) is used to calculate the energy given out by the fuel burnt. A small correction is made to account for the electrical energy input and the burning fuse. After the temperature rise has been measured, the excess pressure in the bomb is released. ## Constant-pressure calorimeter A constant-pressure calorimeter measures the change in enthalpy of a reaction occurring in solution during which the atmospheric pressure remains constant. An example is a coffee-cup calorimeter, which is constructed from two nested Styrofoam cups and holes through which a thermometer and a stirring rod can be inserted. The inner cup holds the solution in which of the reaction occurs, and the outer cup provides insulation. Then Cp = (WDH/(MDT)) where ## Differential scanning calorimeter In a differential scanning calorimeter (DSC), heat flow into a sample—usually contained in a small aluminium capsule or 'pan'—is measured differentially, i.e., by comparing it to the flow into an empty reference pan. In a heat flux DSC, both pans sit on a small slab of material with a known (calibrated) heat resistance K. The temperature of the calorimeter is raised linearly with time (scanned), i.e., the heating rate dT/dt = β is kept constant. This time linearity requires good design and good (computerized) temperature control. Of course, controlled cooling and isothermal experiments are also possible. Heat flows into the two pans by conduction. The flow of heat into the sample is larger because of its heat capacity Cp. The difference in flow dq/dt induces a small temperature difference ΔT across the slab. This temperature difference is measured using a thermocouple. The heat capacity can in principle be determined from this signal: \Delta T = K {dq\over dt} = K C_p\, \beta Note that this formula (equivalent to Newton's law of heat flow) is analogous to, and much older than, Ohm's law of electric flow: ΔV = R dQ/dt = R I. When suddenly heat is absorbed by the sample (e.g., when the sample melts), the signal will respond and exhibit a peak. {dq\over dt} = C_p \beta + f(t,T) From the integral of this peak the enthalpy of melting can be determined, and from its onset the melting temperature. Differential scanning calorimetry is a workhorse technique in many fields, particularly in polymer characterization. A modulated temperature differential scanning calorimeter (MTDSC) is a type of DSC in which a small oscillation is imposed upon the otherwise linear heating rate. This has a number of advantages. It facilitates the direct measurement of the heat capacity in one measurement, even in (quasi-)isothermal conditions. It permits the simultaneous measurement of heat effects that are reversible and not reversible at the timescale of the oscillation (reversing and non-reversing heat flow, respectively). It increases the sensitivity of the heat capacity measurement, allowing for scans at a slow underlying heating rate. ## Isothermal titration calorimeter In an isothermal titration calorimeter, the heat of reaction is used to follow a titration experiment. This permits determination of the mid point (stoichiometry) (N) of a reaction as well as its enthalpy (delta H), entropy (delta S) and of primary concern the binding affinity (Ka) The technique is gaining in importance particularly in the field of biochemistry, because it facilitates determination of substrate binding to enzymes. The technique is commonly used in the pharmaceutical industry to characterize potential drug candidates. ## X-ray microcalorimeter In 1982, a new approach to non-dispersive X-ray spectroscopy, based on the measurement of heat rather than charge, was proposed by Moseley et al. (1984). The detector, and X-ray microcalorimeter, works by sensing the heat pulses generated by X-ray photons when they are absorbed and thermalized. The temperature increase is directly proportional to photon energy. This invention combines high detector efficiency with high energy resolution, mainly achievable because of the low temperature of operation. Microcalorimeters have a low-heat-capacity mass that absorbs incident X-ray (UV, visible, or near IR) photons, a weak link to a low-temperature heat sink which provides the thermal isolation needed for a temperature rise to occur, and a thermometer to measure change in temperature. Following these ideas, a large development effort started. The first astronomical spacecraft that was designed, built and launched with embarqued cryogenic microcalorimeters was Astro-E2. NASA as well as ESA have plans for future missions (Constellation-X and XEUS, respectively) that will use some sort of micro-calorimeters. ## Heat-loss calorimeter ## High-energy particle calorimeter In particle physics, a calorimeter is a component of a detector that measures the energy of entering particles.	Calorimeter Template:Infobox Laboratory equipment A calorimeter is a device used for calorimetry, the science of measuring the heat of chemical reactions or physical changes as well as heat capacity. The word calorimeter is derived from the Latin word calor, meaning heat. Differential scanning calorimeters, isothermal microcalorimeters, titration calorimeters and accelerated rate calorimeters are among the most common types. A simple calorimeter just consists of a thermometer attached to an insulated container. To find the enthalpy change per mole of a substance X in a reaction between two liquids X and Y, they are added to the calorimeter and the initial and final (after the reaction has finished) temperatures are noted. Multiplying the temperature change by the mass and specific heat capacities of the liquids gives a value for the energy given off during the reaction (assuming the reaction was exothermic.). Dividing the energy change by how many moles of X were present gives its enthalpy change of reaction. This method is used primarily in academic teaching as it describes the theory of calorimetry. It doesn’t however account for the heat loss through the container or the heat capacity of the thermometer and container itself. In addition, the object placed inside the calorimeter show that the objects transferred their heat to the calorimeter and into the liquid, and the heat absorbed by the calorimeter and the liquid is equal to the heat given off by the metals. # Types ## Reaction calorimeters A reaction calorimeter is a calorimeter in which a chemical reaction is initiated within a closed insulated container. Reaction heats are measured and the total heat is obtained by integrating heatflow versus time. This is the standard used in industry to measure heats since industrial processes are engineered to run at constant temperatures. Reaction calorimetry can also be used to determine maximum heat release rate for chemical process engineering and for tracking the global kinetics of reactions. There are three common methods for measuring heat in reaction calorimeter: Heat flow calorimetry The cooling/heating jacket controls the temperature of the process. Heat is measured by monitoring the temperature difference between heat transfer fluid and the process fluid as follows: <math>Q = UA(T-t)</math> where Heat flow calorimetry allows the user to measure heat whilst the process temperature remains under control. It is however a difficult technique to use and not particularly accurate. The value of U has to be predetermined by careful experimentation and any change in product composition, liquid level, process temperature, agitation rate or viscosity will upset the calibration. A variation of the 'heat flow' technique is called 'power compensation' calorimetry. This method uses a cooling jacket operating at constant flow and temperature. The process temperature is regulated by adjusting the power of the electrical heater. When the experiment is started, the electrical heat and the cooling power (of the cooling jacket) are in balance. As the process heat load changes, the electrical power is varied in order to maintain the desired process temperature. The heat liberated or absorbed by the process is determined from the difference between the initial electrical power and the demand for electrical power at the time of measurement. The power compensation method is easier to set up than heat flow calorimetry but it suffers from the similar limitations since any change in product composition, liquid level, process temperature, agitation rate or viscosity will upset the calibration. The presence of an electrical heating element is also undesirable for process operations. Heat balance calorimetry The cooling/heating jacket controls the temperature of the process. Heat is measured by monitoring the heat gained or lost by the heat transfer fluid as follows: <math>Q = m_s C_{ps}(T_i - T_o)</math> where Heat balance calorimetry is, in principle, the ideal method of measuring heat since the heat entering and leaving the system through the heating/cooling jacket is measured from the heat transfer fluid (which has known properties). This eliminates most of the calibration problems encountered by heat flow and power compensation calorimetry. Unfortunately, the method does not work well in traditional batch vessels since the process heat signal is obscured by large heat shifts in the cooling/heating jacket. A recent development in calorimetry however is that of constant flux cooling/heating jackets. These use variable geometry cooling jackets and can operate with cooling jackets at substantially constant temperature. These reaction calorimeters tend to be much simpler to use and are much more tolerant of changes in the process conditions (which would affect calibration in heat flow or power compensation calorimeters). ### Bomb calorimeters A bomb calorimeter is a type of constant-volume calorimeter used in measuring the heat of combustion of a particular reaction. Bomb calorimeters have to withstand the large pressure and force of the calorimeter as the reaction is being measured. Electrical energy is used to ignite the fuel, as the fuel is burning, it will heat up the surrounding air, which expands and escapes through a tube that leads the air out of the calorimeter. When the air is escaping through the copper tube it will also heat up the water outside the tube. The temperature of the water allows for calculating calorie content of the fuel. In more recent calorimeter designs, the whole bomb, pressurized with excess pure oxygen (typically at 20atm) and containing a known mass of fuel, is submerged under a known volume of water before the charge is (again electrically) ignited. The bomb, with fuel and oxygen, form a closed system - no air escapes during the reaction. The energy released by the combustion raises the temperature of the steel bomb, its contents, and the surrounding water jacket. The temperature change in the water is then accurately measured. This temperature rise, along with a bomb factor (which is dependent on the heat capacity of the metal bomb parts) is used to calculate the energy given out by the fuel burnt. A small correction is made to account for the electrical energy input and the burning fuse. After the temperature rise has been measured, the excess pressure in the bomb is released. ## Constant-pressure calorimeter A constant-pressure calorimeter measures the change in enthalpy of a reaction occurring in solution during which the atmospheric pressure remains constant. An example is a coffee-cup calorimeter, which is constructed from two nested Styrofoam cups and holes through which a thermometer and a stirring rod can be inserted. The inner cup holds the solution in which of the reaction occurs, and the outer cup provides insulation. Then <math>Cp = (WDH/(MDT))</math> where ## Differential scanning calorimeter In a differential scanning calorimeter (DSC), heat flow into a sample—usually contained in a small aluminium capsule or 'pan'—is measured differentially, i.e., by comparing it to the flow into an empty reference pan. In a heat flux DSC, both pans sit on a small slab of material with a known (calibrated) heat resistance K. The temperature of the calorimeter is raised linearly with time (scanned), i.e., the heating rate dT/dt = β is kept constant. This time linearity requires good design and good (computerized) temperature control. Of course, controlled cooling and isothermal experiments are also possible. Heat flows into the two pans by conduction. The flow of heat into the sample is larger because of its heat capacity Cp. The difference in flow dq/dt induces a small temperature difference ΔT across the slab. This temperature difference is measured using a thermocouple. The heat capacity can in principle be determined from this signal: <math>\Delta T = K {dq\over dt} = K C_p\, \beta</math> Note that this formula (equivalent to Newton's law of heat flow) is analogous to, and much older than, Ohm's law of electric flow: ΔV = R dQ/dt = R I. When suddenly heat is absorbed by the sample (e.g., when the sample melts), the signal will respond and exhibit a peak. <math>{dq\over dt} = C_p \beta + f(t,T) </math> From the integral of this peak the enthalpy of melting can be determined, and from its onset the melting temperature. Differential scanning calorimetry is a workhorse technique in many fields, particularly in polymer characterization. A modulated temperature differential scanning calorimeter (MTDSC) is a type of DSC in which a small oscillation is imposed upon the otherwise linear heating rate. This has a number of advantages. It facilitates the direct measurement of the heat capacity in one measurement, even in (quasi-)isothermal conditions. It permits the simultaneous measurement of heat effects that are reversible and not reversible at the timescale of the oscillation (reversing and non-reversing heat flow, respectively). It increases the sensitivity of the heat capacity measurement, allowing for scans at a slow underlying heating rate. ## Isothermal titration calorimeter In an isothermal titration calorimeter, the heat of reaction is used to follow a titration experiment. This permits determination of the mid point (stoichiometry) (N) of a reaction as well as its enthalpy (delta H), entropy (delta S) and of primary concern the binding affinity (Ka) The technique is gaining in importance particularly in the field of biochemistry, because it facilitates determination of substrate binding to enzymes. The technique is commonly used in the pharmaceutical industry to characterize potential drug candidates. ## X-ray microcalorimeter In 1982, a new approach to non-dispersive X-ray spectroscopy, based on the measurement of heat rather than charge, was proposed by Moseley et al. (1984). The detector, and X-ray microcalorimeter, works by sensing the heat pulses generated by X-ray photons when they are absorbed and thermalized. The temperature increase is directly proportional to photon energy. This invention combines high detector efficiency with high energy resolution, mainly achievable because of the low temperature of operation. Microcalorimeters have a low-heat-capacity mass that absorbs incident X-ray (UV, visible, or near IR) photons, a weak link to a low-temperature heat sink which provides the thermal isolation needed for a temperature rise to occur, and a thermometer to measure change in temperature. Following these ideas, a large development effort started. The first astronomical spacecraft that was designed, built and launched with embarqued cryogenic microcalorimeters was Astro-E2. NASA as well as ESA have plans for future missions (Constellation-X and XEUS, respectively) that will use some sort of micro-calorimeters. ## Heat-loss calorimeter Template:WQA in progress ## High-energy particle calorimeter In particle physics, a calorimeter is a component of a detector that measures the energy of entering particles.	https://www.wikidoc.org/index.php/Calorimeter
eb5c7e030d23b0935043f45790b9ba04a784c007	wikidoc	Osborn wave	Osborn wave Synonyms and keywords: camel-hump sign; late delta wave; hathook junction; hypothermic wave; J point wave; K wave; H wave; current of injury; Osborne wave # Overview Osborn waves (also known as ) are usually observed on the electrocardiogram of people suffering from hypothermia, though they may also occur in people with high blood levels of calcium (hypercalcemia), brain injury, subarachnoid hemorrhage, damage to sympathetic nerves in the neck, and cardiopulmonary arrest from over sedation, vasospastic angina, or ventricular fibrillation. # Historical Perspective The prominent J deflection attributed to hypothermia was first reported in 1938 by Tomaszewski. The wave was observed by others, including Kossmann, Grosse-Brockhoff and Schoedel, Bigelow et al, Juvenelle et al, and Osborn. Over the years, the unusual wave has increasingly been called an Osborn wave, probably because of Osborn's excellent descriptive article written in 1953. Clinicians labeled the deflection an Osborn wave in honor of Osborn, one of the first American Heart Association research fellows. # Causes ## Common Causes - Hypothermia ## Causes of Osborn Waves in Alphabetical Order - Cerebrovascular accident - Coronary vasospasm - Damage to sympathetic nerve chain in the neck after radical neck dissection - Hypercalcemia - Hypothermia - Subarachnoid hemorrhage - Ventricular fibrillation, immediately before and after, often in the setting of vasospastic angina # Diagnosis ## Electrocardiogram The most typical finding is the appearance of the Osborne J wave, an extra deflection between the QRS complex and the T wave. Osborn waves are positive deflections occurring at the junction between the QRS complex and the ST segment, where the S point, also known as the J joint, has a myocardial infarction-like elevation. Osborn waves are more prominent in the left precordial leads. They increases in size with decreasing temperature. They are caused by a current of injury, delayed ventricular depolarization, or early repolarization. Osborn waves may first appear on the ECG for temperatures less tahn 91.4 degrees Fahrenheit (33 degrees Celsius), and consistently appear when when the temperature falls below 25 degrees Centigrade. There is variability in the morphology of Osborn waves as all J wave deflections do not look alike. Some Osborn waves are merely elevations of ST segments in leads V1 and V2, whereas others are of the "spike-and-dome" variety. Given the variability in morphology, a variety of mechanisms may be responsible for the size and shape of J wave deflections. Shown below is an example of the "spike and dome" variant of the Osborn wave: Shown below is an Osborn wave in an 81-year-old male with a core temperature 89.5 degrees F (31.94 C): ## Electrocardiographic Examples ### Examples of Osborn Waves in the Setting of Hypothermia Shown below is the 12 lead ECG of a patient with a body temperature of 32 degrees Celsius. Note the sinus bradycardia, the prolonged QT interval (QTc is not prolonged) and the Osborn J wave, most prominently in leads V2-V5: Shown below is An ECG of a patient with a body temperature of 28 degrees Celsius: Shown below are Osborn J waves due to hypothermia: Shown below are Osborn J waves due to hypothermia: ### Example of Osborn Waves in the Setting of Vasospastic Angina Shown below is the time course of twelve-lead ECG in a 52-year-old man with vasospastic angina. ECGs were obtained prior to the ischemic attack (A), at the onset of chest pressure (B), immediately before ventricular fibrillation (C), after defibrillation and administration of intravenous lidocaine and magnesium (D), and 2 days after the episode (E). Osborn waves (arrowheads) were best seen in the inferior and lateral leads around the occurrence of ventricular fibrillation. In contrast to hypothermic patients, the tracing shows sinus tachycardia and short QT intervals.	Osborn wave Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] Synonyms and keywords: camel-hump sign; late delta wave; hathook junction; hypothermic wave; J point wave; K wave; H wave; current of injury; Osborne wave # Overview Osborn waves (also known as ) are usually observed on the electrocardiogram of people suffering from hypothermia, though they may also occur in people with high blood levels of calcium (hypercalcemia), brain injury, subarachnoid hemorrhage, damage to sympathetic nerves in the neck, and cardiopulmonary arrest from over sedation, vasospastic angina, or ventricular fibrillation. [1] [2] [3] [4] # Historical Perspective The prominent J deflection attributed to hypothermia was first reported in 1938 by Tomaszewski. The wave was observed by others, including Kossmann, Grosse-Brockhoff and Schoedel, Bigelow et al, Juvenelle et al, and Osborn. [5] [6] [7] [8] Over the years, the unusual wave has increasingly been called an Osborn wave, probably because of Osborn's excellent descriptive article written in 1953. Clinicians labeled the deflection an Osborn wave in honor of Osborn, one of the first American Heart Association research fellows. [9] [10] # Causes ## Common Causes - Hypothermia ## Causes of Osborn Waves in Alphabetical Order - Cerebrovascular accident[11] [12] - Coronary vasospasm - Damage to sympathetic nerve chain in the neck after radical neck dissection [13] - Hypercalcemia - Hypothermia - Subarachnoid hemorrhage[14] - Ventricular fibrillation, immediately before and after, often in the setting of vasospastic angina # Diagnosis ## Electrocardiogram The most typical finding is the appearance of the Osborne J wave, an extra deflection between the QRS complex and the T wave. Osborn waves are positive deflections occurring at the junction between the QRS complex and the ST segment, where the S point, also known as the J joint, has a myocardial infarction-like elevation. Osborn waves are more prominent in the left precordial leads. They increases in size with decreasing temperature. They are caused by a current of injury, delayed ventricular depolarization, or early repolarization. Osborn waves may first appear on the ECG for temperatures less tahn 91.4 degrees Fahrenheit (33 degrees Celsius), and consistently appear when when the temperature falls below 25 degrees Centigrade. There is variability in the morphology of Osborn waves as all J wave deflections do not look alike. Some Osborn waves are merely elevations of ST segments in leads V1 and V2, whereas others are of the "spike-and-dome" variety. Given the variability in morphology, a variety of mechanisms may be responsible for the size and shape of J wave deflections. Shown below is an example of the "spike and dome" variant of the Osborn wave: Shown below is an Osborn wave in an 81-year-old male with a core temperature 89.5 degrees F (31.94 C): ## Electrocardiographic Examples ### Examples of Osborn Waves in the Setting of Hypothermia Shown below is the 12 lead ECG of a patient with a body temperature of 32 degrees Celsius. Note the sinus bradycardia, the prolonged QT interval (QTc is not prolonged) and the Osborn J wave, most prominently in leads V2-V5: Shown below is An ECG of a patient with a body temperature of 28 degrees Celsius: Shown below are Osborn J waves due to hypothermia: Shown below are Osborn J waves due to hypothermia: ### Example of Osborn Waves in the Setting of Vasospastic Angina Shown below is the time course of twelve-lead ECG in a 52-year-old man with vasospastic angina. ECGs were obtained prior to the ischemic attack (A), at the onset of chest pressure (B), immediately before ventricular fibrillation (C), after defibrillation and administration of intravenous lidocaine and magnesium (D), and 2 days after the episode (E). Osborn waves (arrowheads) were best seen in the inferior and lateral leads around the occurrence of ventricular fibrillation. In contrast to hypothermic patients, the tracing shows sinus tachycardia and short QT intervals.[15]	https://www.wikidoc.org/index.php/Camel-hump_sign
6316b436ea584d1a0d336820143048383efdb099	wikidoc	Canakinumab	Canakinumab # 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 Canakinumab is a monoclonal antibody that is FDA approved for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), Systemic Juvenile Idiopathic Arthritis (SJIA). Common adverse reactions include Injection site reaction, diarrhea, gastroenteritis , nausea , upper abdominal pain (systemic juvenile idiopathic arthritis, Infectious disease (systemic juvenile idiopathic arthritis, musculoskeletal pain, headache, vertigo, bronchitis, nasopharyngitis , pharyngitis, rhinitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ILARIS (canakinumab) is an interleukin-1β blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older including: - Muckle-Wells Syndrome (MWS) - ILARIS is indicated for the treatment of active Systemic Juvenile Idiopathic Arthritis (SJIA) in patients aged 2 years and older. - INJECTION FOR SUBCUTANEOUS USE ONLY. - The recommended dose of ILARIS is 150 mg for CAPS patients with body weight greater than 40 kg. For CAPS patients with body weight greater than or equal to 15 kg and less than or equal to 40 kg, the recommended dose is 2 mg/kg. - For children 15 to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg. - ILARIS is administered every eight weeks as a single dose via subcutaneous injection. - The recommended dose of ILARIS for SJIA patients with a body weight greater than or equal to 7.5 kg is 4 mg/kg (with a maximum of 300 mg) administered every 4 weeks via subcutaneous injection. - STEP 1: Using aseptic technique, reconstitute each vial of ILARIS by slowly injecting 1 mL of preservative-free Sterile Water for Injection with a 1 mL syringe and an 18 gauge x 2” needle. - STEP 2: Swirl the vial slowly at an angle of about 45° for approximately 1 minute and allow to stand for 5 minutes. Do not shake. Then gently turn the vial upside down and back again ten times. Avoid touching the rubber stopper with your fingers. - STEP 3: Allow to stand for about 15 minutes at room temperature to obtain a clear solution. The reconstituted solution has a final concentration of 150 mg/mL. Do not shake. Do not use if particulate matter is present in the solution. Tap the side of the vial to remove any residual liquid from the stopper. The reconstituted solution should be essentially free from particulates, and clear to opalescent. The solution should be colorless or may have a slight brownish-yellow tint. If the solution has a distinctly brown discoloration it should not be used. If not used within 60 minutes of reconstitution, the solution should be stored in the refrigerator at 2°C to 8°C (36°F to 46°F) and used within 4 hours. Slight foaming of the product upon reconstitution is not unusual. - STEP 4: Using a sterile syringe and needle carefully withdraw the required volume depending on the dose to be administered (0.2 mL to 1 mL) and subcutaneously inject using a 27 gauge x 0.5” needle. - Injection into scar tissue should be avoided as this may result in insufficient exposure to ILARIS. - ILARIS 180 mg powder for solution for injection is supplied in a single-use vial. Any unused product or waste material should be disposed of in accordance with local requirements. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Canakinumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Canakinumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Canakinumab in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Canakinumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Canakinumab in pediatric patients. # Contraindications - Confirmed hypersensitivity to the active substance or to any of the excipients # Warnings - ILARIS has been associated with an increased risk of serious infections. Physicians should exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. ILARIS should not be administered to patients during an active infection requiring medical intervention. Administration of ILARIS should be discontinued if a patient develops a serious infection. - Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported with ILARIS. Generally, the observed infections responded to standard therapy. Isolated cases of unusual or opportunistic infections (e.g., aspergillosis, atypical mycobacterial infections, cytomegalovirus, herpes zoster) were reported during ILARIS treatment. A causal relationship of ILARIS to these events cannot be excluded. In clinical trials, ILARIS has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Coadministration of ILARIS with TNF inhibitors is not recommended because this may increase the risk of serious infections. - Drugs that affect the immune system by blocking TNF have been associated with an increased risk of new tuberculosis and reactivation of latent tuberculosis (TB). It is possible that use of IL-1 inhibitors such as ILARIS increases the risk of reactivation of tuberculosis or of opportunistic infections. - Prior to initiating immunomodulatory therapies, including ILARIS, patients should be evaluated for active and latent tuberculosis infection. Appropriate screening tests should be performed in all patients. ILARIS has not been studied in patients with a positive tuberculosis screen, and the safety of ILARIS in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated according to standard medical practice prior to therapy with ILARIS. All patients should be instructed to seek medical advice if signs, symptoms, or high risk exposure suggestive of tuberculosis (e.g., persistent cough, weight loss, subfebrile temperature) appear during or after ILARIS therapy. - Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with ILARIS. - The impact of treatment with anti-interleukin-1 (IL-1) therapy on the development of malignancies is not known. However, treatment with immunosuppressants, including ILARIS, may result in an increase in the risk of malignancies. - Hypersensitivity reactions have been reported with ILARIS therapy. During clinical trials, no anaphylactic reactions have been reported. It should be recognized that symptoms of the underlying disease being treated may be similar to symptoms of hypersensitivity. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS. - Live vaccines should not be given concurrently with ILARIS. Since no data are available on either the efficacy or on the risks of secondary transmission of infection by live vaccines in patients receiving ILARIS, live vaccines should not be given concurrently with ILARIS. In addition, because ILARIS may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ILARIS. No data are available on the effectiveness of vaccinations with inactivated (killed) antigens in patients receiving ILARIS. - Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ILARIS, adult and pediatric patients receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine. - Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with rheumatic conditions, in particular SJIA, and should be aggressively treated. Physicians should be attentive to symptoms of infection or worsening of SJIA, as these are known triggers for MAS. Eleven cases of MAS were observed in 201 SJIA patients treated with canakinumab in clinical trials. Based on the clinical trial experience, ILARIS does not appear to increase the incidence of MAS in SJIA patients, but no definitive conclusion can be made. # Adverse Reactions ## Clinical Trials Experience - Three hundred ninety-five patients, including approximately 250 children (aged 2 to 17 years) have been treated with ILARIS in interventional trials in CAPS or SJIA. The most frequently reported adverse drug reactions were infections predominantly of the upper respiratory tract. The majority of the events were mild to moderate although serious infections were observed. The type and frequency of adverse drug reactions appeared to be consistent over time. - Opportunistic infections have also been reported in patients treated with ILARIS. - 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 data described herein reflect exposure to ILARIS in 104 adult and pediatric CAPS patients, including 20 FCAS, 72 MWS, 10 MWS/NOMID (Neonatal Onset Multisystem Inflammatory Disorder) overlap, 1 non-FCAS non-MWS, and 1 misdiagnosed in placebo-controlled (35 patients) and uncontrolled trials. Sixty-two patients were exposed to ILARIS for at least 6 months, 56 for at least 1 year and 4 for at least 3 years. A total of 9 serious adverse reactions were reported for CAPS patients. Among these were vertigo (2 patients), infections (3 patients), including intra-abdominal abscess following appendectomy (1 patient). The most commonly reported adverse reactions associated with ILARIS treatment in the CAPS patients were nasopharyngitis, diarrhea, influenza, headache, and nausea. One patient discontinued treatment due to potential infection. - CAPS Study 1 investigated the safety of ILARIS in an 8-week, open-label period (Part 1), followed by a 24-week, randomized withdrawal period (Part 2), followed by a 16-week, open-label period (Part 3). All patients were treated with ILARIS 150 mg subcutaneously or 2 mg/kg if body weight was greater than or equal to 15 kg and less than or equal to 40 kg (see Table 1). - Since all CAPS patients received ILARIS in Part 1, there are no controlled data on adverse events (AEs). Data in Table 1 are for all AEs for all CAPS patients receiving canakinumab. In CAPS Study 1, no pattern was observed for any type or frequency of adverse events throughout the three study periods. - Vertigo has been reported in 9% to 14% of patients in CAPS studies, exclusively in MWS patients, and reported as a serious adverse event in two cases. All events resolved with continued treatment with ILARIS. - In CAPS Study 1, subcutaneous injection site reactions were observed in 9% of patients in Part 1 with mild tolerability reactions; in Part 2, one patient each (7%) had a mild or a moderate tolerability reaction and, in Part 3, one patient had a mild local tolerability reaction. No severe injection-site reactions were reported and none led to discontinuation of treatment. - A total of 201 SJIA patients aged 2 to less than 20 years have received ILARIS in clinical trials. The safety of ILARIS compared to placebo was investigated in two phase 3 studies. Patients in SJIA Study 1 received a single dose of ILARIS 4 mg/kg (n=43) or placebo (n=41) via subcutaneous injection and were assessed at Day 15 for the efficacy endpoints and had a safety analysis up to Day 29. SJIA Study 2 was a two-part study with an open-label, single-arm active treatment period (Part I) followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design (Part II). Overall, 177 patients were enrolled into the study and received ILARIS 4 mg/kg (up to 300 mg maximum) in Part I, and 100 patients received ILARIS 4 mg/kg (up to 300 mg maximum) every 4 weeks or placebo in Part II. Adverse drug reactions listed in Table 2 showed higher rates than placebo from both trials. The adverse drug reactions associated with ILARIS treatment in SJIA patients were infections, abdominal pain, and injection site reactions. Serious infections (e.g., pneumonia, varicella, gastroenteritis, measles, sepsis, otitis media, sinusitis, adenovirus, lymph node abscess, pharyngitis) were observed in approximately 4% to 5% (0.02 to 0.17 per 100 patient-days) of patients receiving ILARIS in both studies. - Adverse reactions are listed according to MedDRA version 15.0 system organ class. - During clinical trials, no anaphylactic reactions have been reported. In CAPS trials one patient discontinued and in SJIA trials no patients discontinued due to hypersensitivity reactions. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS. - A biosensor binding assay or a bridging immunoassay was used to detect antibodies directed against canakinumab in patients who received ILARIS. Antibodies against ILARIS were observed in approximately 1.5% and 3.1% of the patients treated with ILARIS for CAPS and SJIA, respectively. No neutralizing antibodies were detected. No apparent correlation of antibody development to clinical response or adverse events was observed. The CAPS clinical studies employed the biosensor binding assay, and most of the SJIA clinical studies employed the bridging assay. The data obtained in an assay are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, underlying disease, and the number of patients tested. For these reasons, comparison of the incidence of antibodies to canakinumab between the CAPS and SJIA clinical studies or with the incidence of antibodies to other products may be misleading. - During clinical trials with ILARIS, mean values decreased for white blood cells, neutrophils and platelets. - In the randomized, placebo-controlled portion of SJIA Study 2 decreased white blood cell counts (WBC) less than or equal to 0.8 times lower limit of normal (LLN) were reported in 5 patients (10.4%)in the ILARIS group compared to 2 (4.0%) in the placebo group. Transient decreases in absolute neutrophil count (ANC) to less than 1x109/L were reported in 3 patients (6.0%) in the ILARIS group compared to1 patient (2.0%) in the placebo group. One case of ANC less than 0.5x109/L was observed in the ILARIS group and none in the placebo group. - Mild (less than LLN and greater than 75x109/L) and transient decreases in platelet counts were observed in 3 (6.3%) ILARIS treated patients versus 1 (2.0%) placebo-treated patient. - Elevations of transaminases have been observed in patients treated with ILARIS. - In the randomized, placebo-controlled portion of SJIA Study 2, high ALT and/or AST greater than or equal to 3 times upper limit of normal (ULN) were reported in 2 (4.1%) ILARIS-treated patients and 1 (2.0%) placebo patient. All patients had normal values at the next visit. - Asymptomatic and mild elevations of serum bilirubin have been observed in patients treated with ILARIS without concomitant elevations of transaminases. ## Postmarketing Experience There is limited information regarding Canakinumab Postmarketing Experience in the drug label. # Drug Interactions - Interactions between ILARIS and other medicinal products have not been investigated in formal studies. - An increased incidence of serious infections and an increased risk of neutropenia have been associated with administration of another IL-1 blocker in combination with TNF inhibitors in another patient population. Use of ILARIS with TNF inhibitors may also result in similar toxicities and is not recommended because this may increase the risk of serious infections. - The concomitant administration of ILARIS with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacological interactions between ILARIS and a recombinant IL-1ra, concomitant administration of ILARIS and other agents that block IL-1 or its receptors is not recommended. - No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving ILARIS. Therefore, live vaccines should not be given concurrently with ILARIS. It is recommended that, if possible, pediatric and adult patients should complete all immunizations in accordance with current immunization guidelines prior to initiating ILARIS therapy. - The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as canakinumab, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of canakinumab, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed and the individual dose of the medicinal product may need to be adjusted as needed. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Canakinumab has been shown to produce delays in fetal skeletal development when evaluated in marmoset monkeys using doses 11-fold the maximum recommended human dose (MRHD) and greater (based on a plasma area under the time-concentration curve comparison). Doses producing exposures within the clinical exposure range at the MRHD were not evaluated. Similar delays in fetal skeletal development were observed in mice administered a murine analog of canakinumab. There are no adequate and well-controlled studies of ILARIS 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. - Embryofetal developmental toxicity studies were performed in marmoset monkeys and mice. Pregnant marmoset monkeys were administered canakinumab subcutaneously twice-weekly at doses of 15, 50, or 150 mg/kg (representing 11- to 110-fold the human dose based on a plasma AUC comparison at the MRHD) from gestation days 25 to 109 which revealed no evidence of embryotoxicity or fetal malformations. There were increases in the incidence of incomplete ossification of the terminal caudal vertebra and misaligned and/or bipartite vertebra in fetuses at all dose levels when compared to concurrent controls suggestive of delay in skeletal development in the marmoset. Since canakinumab does not cross-react with mouse or rat IL-1, pregnant mice were subcutaneously administered a murine analog of canakinumab at doses of 15, 50, or 150 mg/kg on gestation days 6, 11, and 17. The incidence of incomplete ossification of the parietal and frontal skull bones of fetuses was increased in a dose-dependent manner at all dose levels tested. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Canakinumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Canakinumab during labor and delivery. ### Nursing Mothers - It is not known whether canakinumab is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ILARIS is administered to a nursing woman. ### Pediatric Use - The CAPS trials with ILARIS included a total of 23 pediatric patients with an age range from 4 years to 17 years (11 adolescents were treated subcutaneously with 150 mg , and 12 children were treated with 2 mg/kg based on body weight greater than or equal to 15 kg and less than or equal to 40 kg). The majority of patients achieved improvement in clinical symptoms and objective markers of inflammation (e.g., Serum Amyloid A and C-Reactive Protein). Overall, the efficacy and safety of ILARIS in pediatric and adult patients were comparable. Infections of the upper respiratory tract were the most frequently reported infection. The safety and effectiveness of ILARIS in CAPS patients under 4 years of age has not been established ### Geriatic Use - Clinical studies of ILARIS did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Canakinumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Canakinumab with respect to specific racial populations. ### Renal Impairment No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with renal impairment. ### Hepatic Impairment No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Canakinumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Canakinumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Canakinumab in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Canakinumab in the drug label. # Overdosage - No confirmed case of overdose has been reported. In the case of overdose, it is recommended that the subject be monitored for any signs and symptoms of adverse reactions or effects, and appropriate symptomatic treatment be instituted immediately. # Pharmacology ## Mechanism of Action - Canakinumab is a human monoclonal anti-human IL-1β antibody of the IgG1/κ isotype. Canakinumab binds to human IL-1β and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). - CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 gene (also known as Cold-Induced Auto-inflammatory Syndrome-1 ). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis. The NLRP-3 gene encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation. Systemic juvenile idiopathic arthritis (SJIA) is a severe autoinflammatory disease, driven by innate immunity by means of pro-inflammatory cytokines such as interleukin 1β (IL-1β). ## Structure - Canakinumab is a recombinant, human anti-human-IL-1β monoclonal antibody that belongs to the IgG1/κ isotype subclass. It is expressed in a murine Sp2/0-Ag14 cell line and comprised of two 447- (or 448-) residue heavy chains and two 214-residue light chains, with a molecular mass of 145157 Daltons when deglycosylated. Both heavy chains of canakinumab contain oligosaccharide chains linked to the protein backbone at asparagine 298 (Asn 298). - The biological activity of canakinumab is measured by comparing its inhibition of IL-1β-dependent expression of the reporter gene luciferase to that of a canakinumab internal reference standard, using a stably transfected cell line. - ILARIS is supplied in a sterile, single-use, colorless, 6 mL glass vial with coated stopper and aluminum flip-off cap. Each vial contains 180 mg of canakinumab as a white, preservative-free, lyophilized powder. Reconstitution with 1 mL of preservative-free Sterile Water for Injection is required prior to subcutaneous administration of the drug. The reconstituted canakinumab is a 150 mg/mL solution essentially free of particulates, clear to slightly opalescent, and is colorless or may have a slightly brownish-yellow tint. A volume of up to 1 mL can be withdrawn for delivery of 150 mg/mL canakinumab for subcutaneous administration. Each reconstituted vial contains 180 mg canakinumab, sucrose, L-histidine, L-histidine HCL monohydrate, polysorbate 80 and Sterile Water for Injection. No preservatives are present. ## Pharmacodynamics - C-reactive protein and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Following ILARIS treatment, CRP and SAA levels normalize within 8 days. In SJIA the median percent reduction in CRP from baseline to Day 15 was 91%. Improvement in pharmacodynamic markers may not be representative of clinical response. ## Pharmacokinetics - The peak serum canakinumab concentration (Cmax) of 16 ± 3.5 mcg/mL occurred approximately 7 days after subcutaneous administration of a single, 150 mg dose subcutaneously to adult CAPS patients. The mean terminal half-life was 26 days. The absolute bioavailability of subcutaneous canakinumab was estimated to be 66%. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 0.30 to 10 mg/kg given as intravenous infusion or from 150 to 300 mg as subcutaneous injection. - Canakinumab binds to serum IL-1β. Canakinumab volume of distribution (Vss) varied according to body weight and was estimated to be 6.01 liters in a typical CAPS patient weighing 70 kg, and 3.2 liters in a SJIA patient weighing 33 kg. The expected accumulation ratio was 1.3-fold for CAPS patients and 1.6-fold for SJIA patients following 6 months of subcutaneous dosing of 150 mg ILARIS every 8 weeks and 4 mg/kg every 4 weeks, respectively. - Clearance (CL) of canakinumab varied according to body weight and was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg and 0.11 L/day in a SJIA patient weighing 33 kg. There was no indication of accelerated clearance or time-dependent change in the pharmacokinetic properties of canakinumab following repeated administration. No gender- or age-related pharmacokinetic differences were observed after correction for body weight. - Pharmacokinetic properties are similar in CAPS and SJIA pediatric populations. - In CAPS patients, peak concentrations of canakinumab occurred between 2 to 7 days following single subcutaneous administration of ILARIS 150 mg or 2 mg/kg in pediatric patients. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokinetic properties observed in adults. - In SJIA, exposure parameters (such as AUC and Cmax) were comparable across age groups from 2 years of age and above following subcutaneous administration of canakinumab 4 mg/kg every 4 weeks. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential of canakinumab. - The mutagenic potential of canakinumab was not evaluated. - As canakinumab does not cross-react with rodent IL-1β, male and female fertility was evaluated in a mouse model using a murine analog of canakinumab. Male mice were treated weekly beginning 4 weeks prior to mating and continuing through 3 weeks after mating. Female mice were treated weekly for 2 weeks prior to mating through gestation day 3 or 4. The murine analog of canakinumab did not alter either male or female fertility parameters at subcutaneous doses up to 150 mg/kg. # Clinical Studies - The efficacy and safety of ILARIS for the treatment of CAPS was demonstrated in CAPS Study 1, a 3-part trial in patients 9 to 74 years of age with the MWS phenotype of CAPS. Throughout the trial, patients weighing more than 40 kg received ILARIS 150 mg and patients weighing 15 to 40 kg received 2 mg/kg. Part 1 was an 8-week open-label, single-dose period where all patients received ILARIS. Patients who achieved a complete clinical response and did not relapse by Week 8 were randomized into Part 2, a 24-week randomized, double-blind, placebo-controlled withdrawal period. Patients who completed Part 2 or experienced a disease flare entered Part 3, a 16-week open-label active treatment phase. A complete response was defined as ratings of minimal or better for physician’s assessment of disease activity (PHY) and assessment of skin disease (SKD) and had serum levels of C-Reactive Protein (CRP) and Serum Amyloid A (SAA) less than 10 mg/L. A disease flare was defined as a CRP and/or SAA values greater than 30 mg/L and either a score of mild or worse for PHY or a score of minimal or worse for PHY and SKD. - In Part 1, a complete clinical response was observed in 71% of patients one week following initiation of treatment and in 97% of patients by Week 8 (see Figure 1 and Table 3). In the randomized withdrawal period, a total of 81% of the patients randomized to placebo flared as compared to none (0%) of the patients randomized to ILARIS. The 95% confidence interval for treatment difference in the proportion of flares was 53% to 96%. At the end of Part 2, all 15 patients treated with ILARIS had absent or minimal disease activity and skin disease (see Table 3). - In a second trial, patients 4 to 74 years of age with both MWS and FCAS phenotypes of CAPS were treated in an open-label manner. Treatment with ILARIS resulted in clinically significant improvement of signs and symptoms and in normalization of high CRP and SAA in a majority of patients within 1 week. - The efficacy of ILARIS for the treatment of active SJIA was assessed in 2 phase 3 studies (SJIA Study 1 and SJIA Study 2). Patients enrolled were aged 2 to less than 20 years (mean age at baseline: 8.5 years) with a confirmed diagnosis of SJIA at least 2 months before enrollment (mean disease duration at baseline: 3.5 years). Patients had active disease defined as greater than or equal to 2 joints with active arthritis (mean number of active joints at baseline: 15.4), documented spiking, intermittent fever (body temperature greater than 38°C) for at least 1 day within 1 week before study drug administration, and CRP greater than 30 mg/L (normal range less than 10 mg/L)(mean CRP at baseline: 200.5 mg/L). Patients were allowed to continue their stable dose of methotrexate, corticosteroids, and/or NSAIDs without change, except for tapering of the corticosteroid dose as per study design in SJIA Study 2 (see below). - SJIA Study 1 was a randomized, double-blind, placebo-controlled, single-dose 4-week study assessing the short term efficacy of ILARIS in 84 patients randomized to receive a single subcutaneous dose of 4 mg/kg ILARIS or placebo (43 patients received ILARIS and 41 patients received placebo). The primary objective of this study was to demonstrate the superiority of ILARIS versus placebo in the proportion of patients who achieved at least 30% improvement in an adapted pediatric American College of Rheumatology (ACR) response criterion which included both the pediatric ACR core set (ACR30 response) and absence of fever (temperature less than or equal to 38°C in the preceding 7 days) at Day 15. - Pediatric ACR responses are defined by achieving levels of percentage improvement (30%, 50%, and 70%) from baseline in at least 3 of the 6 core outcome variables, with worsening of greater than or equal to 30% in no more than one of the remaining variables. Core outcome variables included a physician global assessment of disease activity, parent or patient global assessment of wellbeing, number of joints with active arthritis, number of joints with limited range of motion, CRP, and functional ability (Childhood Health Assessment Questionnaire-CHAQ). - Percentages of patients by pediatric ACR response are presented in Table 4. - Results for the components of the pediatric ACR core set were consistent with the overall ACR response results, for systemic and arthritic components including the reduction in the total number of active joints and joints with limited range of motion. Among the patients who returned for a Day 15 visit, the mean change in patient pain score (0 to 100 mm visual analogue scale) was -50.0 mm on ILARIS (N=43), as compared to +4.5 mm on placebo (N=25). The mean change in pain score among ILARIS treated patients was consistent through Day 29. All patients treated with ILARIS had no fever at Day 3 compared to 87% of patients treated with placebo. - SJIA Study 2 was a randomized, double-blind, placebo-controlled, withdrawal study of flare prevention by ILARIS in patients with active SJIA. Flare was defined by worsening of greater than or equal to 30% in at least 3 of the 6 core Pediatric ACR response variables combined with improvement of greater than or equal to 30% in no more than 1 of the 6 variables, or reappearance of fever not due to infection for at least 2 consecutive days. The study consisted of 2 major parts. One hundred seventy-seven patients were enrolled in the study and received 4 mg/kg ILARIS subcutaneously every 4 weeks in Part I and 100 of these patients continued into Part II to receive either ILARIS 4 mg/kg or placebo subcutaneously every 4 weeks. - Of the total 128 patients who entered the open-label portion of Study 2 taking corticosteroids, 92 attempted corticosteroid tapering. Fifty-seven (62%) of the 92 patients who attempted to taper were able to successfully taper their corticosteroid dose and 42 (46%) discontinued corticosteroids. - Time to Flare - Part II was a randomized withdrawal design to demonstrate that the time to flare was longer with ILARIS than with placebo. Follow-up stopped when 37 events had been observed resulting in patients being followed for different lengths of time. The probability of experiencing a flare over time in Part II was statistically lower for the ILARIS treatment group than for the placebo group (Figure 2). This corresponded to a 64% relative reduction in the risk of flare for patients in the ILARIS group as compared to those in the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75). # How Supplied - Carton of 1 vial………………………………………………………………………………………….NDC 0078-0582-61 - Each single-use vial of ILARIS contains a sterile, preservative free, white lyophilized powder containing 180 mg of canakinumab. Each vial is to be reconstituted with 1 mL of preservative-free Sterile Water for Injection resulting in a final concentration of 150 mg/mL. ## Storage - The unopened vial must be stored refrigerated at 2°C to 8°C (36°F to 46° F). Do not freeze. Store in the original carton to protect from light. Do not use beyond the date stamped on the label. After reconstitution, ILARIS should be kept from light, and can be kept at room temperature if used within 60 minutes of reconstitution. Otherwise, it should be refrigerated at 2°C to 8°C (36°F to 46°F) and used within 4 hours of reconstitution. ILARIS does not contain preservatives. Unused portions of ILARIS should be discarded. - Keep this and all drugs out of the reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised of the potential benefits and risks of ILARIS. Physicians should instruct their patients to read the Medication Guide before starting ILARIS therapy. - Patients should be advised that healthcare providers should perform administration of ILARIS, by the subcutaneous injection route. - Patients should be cautioned that ILARIS use has been associated with serious infections. Patients should be counseled to contact their healthcare professional immediately if they develop an infection after starting ILARIS. Treatment with ILARIS should be discontinued if a patient develops a serious infection. Patients should be counseled not to take any IL-1 blocking drug, including ILARIS, if they are also taking a drug that blocks TNF such as etanercept, infliximab, or adalimumab. Use of ILARIS with other IL-1 blocking agents, such as rilonacept and anakinra is not recommended. Patients should be cautioned not to receive ILARIS if they have a chronic or active infection, including HIV, Hepatitis B or Hepatitis C. - Prior to initiation of therapy with ILARIS, physicians should review with adult and pediatric patients their vaccination history relative to current medical guidelines for vaccine use, including taking into account the potential of increased risk of infection during treatment with ILARIS. - Physicians should explain to patients that a very small number of patients in the clinical trials experienced a reaction at the subcutaneous injection site. Injection-site reactions may include pain, erythema, swelling, pruritus, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Healthcare providers should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician. - Patients should be counseled to contact their healthcare provider immediately if they develop signs of allergic reaction such as difficulty breathing or swallowing, nausea, dizziness, skin rash, itching, hives, palpitations or low blood pressure. # Precautions with Alcohol - Alcohol-Canakinumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ILARIS® # Look-Alike Drug Names There is limited information regarding Canakinumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Canakinumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, 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 Canakinumab is a monoclonal antibody that is FDA approved for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), Systemic Juvenile Idiopathic Arthritis (SJIA). Common adverse reactions include Injection site reaction, diarrhea, gastroenteritis , nausea , upper abdominal pain (systemic juvenile idiopathic arthritis, Infectious disease (systemic juvenile idiopathic arthritis, musculoskeletal pain, headache, vertigo, bronchitis, nasopharyngitis , pharyngitis, rhinitis. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - ILARIS (canakinumab) is an interleukin-1β blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), in adults and children 4 years of age and older including: - Muckle-Wells Syndrome (MWS) - ILARIS is indicated for the treatment of active Systemic Juvenile Idiopathic Arthritis (SJIA) in patients aged 2 years and older. - INJECTION FOR SUBCUTANEOUS USE ONLY. - The recommended dose of ILARIS is 150 mg for CAPS patients with body weight greater than 40 kg. For CAPS patients with body weight greater than or equal to 15 kg and less than or equal to 40 kg, the recommended dose is 2 mg/kg. - For children 15 to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg. - ILARIS is administered every eight weeks as a single dose via subcutaneous injection. - The recommended dose of ILARIS for SJIA patients with a body weight greater than or equal to 7.5 kg is 4 mg/kg (with a maximum of 300 mg) administered every 4 weeks via subcutaneous injection. - STEP 1: Using aseptic technique, reconstitute each vial of ILARIS by slowly injecting 1 mL of preservative-free Sterile Water for Injection with a 1 mL syringe and an 18 gauge x 2” needle. - STEP 2: Swirl the vial slowly at an angle of about 45° for approximately 1 minute and allow to stand for 5 minutes. Do not shake. Then gently turn the vial upside down and back again ten times. Avoid touching the rubber stopper with your fingers. - STEP 3: Allow to stand for about 15 minutes at room temperature to obtain a clear solution. The reconstituted solution has a final concentration of 150 mg/mL. Do not shake. Do not use if particulate matter is present in the solution. Tap the side of the vial to remove any residual liquid from the stopper. The reconstituted solution should be essentially free from particulates, and clear to opalescent. The solution should be colorless or may have a slight brownish-yellow tint. If the solution has a distinctly brown discoloration it should not be used. If not used within 60 minutes of reconstitution, the solution should be stored in the refrigerator at 2°C to 8°C (36°F to 46°F) and used within 4 hours. Slight foaming of the product upon reconstitution is not unusual. - STEP 4: Using a sterile syringe and needle carefully withdraw the required volume depending on the dose to be administered (0.2 mL to 1 mL) and subcutaneously inject using a 27 gauge x 0.5” needle. - Injection into scar tissue should be avoided as this may result in insufficient exposure to ILARIS. - ILARIS 180 mg powder for solution for injection is supplied in a single-use vial. Any unused product or waste material should be disposed of in accordance with local requirements. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Canakinumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Canakinumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Canakinumab in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Canakinumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Canakinumab in pediatric patients. # Contraindications - Confirmed hypersensitivity to the active substance or to any of the excipients # Warnings - ILARIS has been associated with an increased risk of serious infections. Physicians should exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. ILARIS should not be administered to patients during an active infection requiring medical intervention. Administration of ILARIS should be discontinued if a patient develops a serious infection. - Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported with ILARIS. Generally, the observed infections responded to standard therapy. Isolated cases of unusual or opportunistic infections (e.g., aspergillosis, atypical mycobacterial infections, cytomegalovirus, herpes zoster) were reported during ILARIS treatment. A causal relationship of ILARIS to these events cannot be excluded. In clinical trials, ILARIS has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Coadministration of ILARIS with TNF inhibitors is not recommended because this may increase the risk of serious infections. - Drugs that affect the immune system by blocking TNF have been associated with an increased risk of new tuberculosis and reactivation of latent tuberculosis (TB). It is possible that use of IL-1 inhibitors such as ILARIS increases the risk of reactivation of tuberculosis or of opportunistic infections. - Prior to initiating immunomodulatory therapies, including ILARIS, patients should be evaluated for active and latent tuberculosis infection. Appropriate screening tests should be performed in all patients. ILARIS has not been studied in patients with a positive tuberculosis screen, and the safety of ILARIS in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated according to standard medical practice prior to therapy with ILARIS. All patients should be instructed to seek medical advice if signs, symptoms, or high risk exposure suggestive of tuberculosis (e.g., persistent cough, weight loss, subfebrile temperature) appear during or after ILARIS therapy. - Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with ILARIS. - The impact of treatment with anti-interleukin-1 (IL-1) therapy on the development of malignancies is not known. However, treatment with immunosuppressants, including ILARIS, may result in an increase in the risk of malignancies. - Hypersensitivity reactions have been reported with ILARIS therapy. During clinical trials, no anaphylactic reactions have been reported. It should be recognized that symptoms of the underlying disease being treated may be similar to symptoms of hypersensitivity. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS. - Live vaccines should not be given concurrently with ILARIS. Since no data are available on either the efficacy or on the risks of secondary transmission of infection by live vaccines in patients receiving ILARIS, live vaccines should not be given concurrently with ILARIS. In addition, because ILARIS may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ILARIS. No data are available on the effectiveness of vaccinations with inactivated (killed) antigens in patients receiving ILARIS. - Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ILARIS, adult and pediatric patients receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine. - Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with rheumatic conditions, in particular SJIA, and should be aggressively treated. Physicians should be attentive to symptoms of infection or worsening of SJIA, as these are known triggers for MAS. Eleven cases of MAS were observed in 201 SJIA patients treated with canakinumab in clinical trials. Based on the clinical trial experience, ILARIS does not appear to increase the incidence of MAS in SJIA patients, but no definitive conclusion can be made. # Adverse Reactions ## Clinical Trials Experience - Three hundred ninety-five patients, including approximately 250 children (aged 2 to 17 years) have been treated with ILARIS in interventional trials in CAPS or SJIA. The most frequently reported adverse drug reactions were infections predominantly of the upper respiratory tract. The majority of the events were mild to moderate although serious infections were observed. The type and frequency of adverse drug reactions appeared to be consistent over time. - Opportunistic infections have also been reported in patients treated with ILARIS. - 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 data described herein reflect exposure to ILARIS in 104 adult and pediatric CAPS patients, including 20 FCAS, 72 MWS, 10 MWS/NOMID (Neonatal Onset Multisystem Inflammatory Disorder) overlap, 1 non-FCAS non-MWS, and 1 misdiagnosed in placebo-controlled (35 patients) and uncontrolled trials. Sixty-two patients were exposed to ILARIS for at least 6 months, 56 for at least 1 year and 4 for at least 3 years. A total of 9 serious adverse reactions were reported for CAPS patients. Among these were vertigo (2 patients), infections (3 patients), including intra-abdominal abscess following appendectomy (1 patient). The most commonly reported adverse reactions associated with ILARIS treatment in the CAPS patients were nasopharyngitis, diarrhea, influenza, headache, and nausea. One patient discontinued treatment due to potential infection. - CAPS Study 1 investigated the safety of ILARIS in an 8-week, open-label period (Part 1), followed by a 24-week, randomized withdrawal period (Part 2), followed by a 16-week, open-label period (Part 3). All patients were treated with ILARIS 150 mg subcutaneously or 2 mg/kg if body weight was greater than or equal to 15 kg and less than or equal to 40 kg (see Table 1). - Since all CAPS patients received ILARIS in Part 1, there are no controlled data on adverse events (AEs). Data in Table 1 are for all AEs for all CAPS patients receiving canakinumab. In CAPS Study 1, no pattern was observed for any type or frequency of adverse events throughout the three study periods. - Vertigo has been reported in 9% to 14% of patients in CAPS studies, exclusively in MWS patients, and reported as a serious adverse event in two cases. All events resolved with continued treatment with ILARIS. - In CAPS Study 1, subcutaneous injection site reactions were observed in 9% of patients in Part 1 with mild tolerability reactions; in Part 2, one patient each (7%) had a mild or a moderate tolerability reaction and, in Part 3, one patient had a mild local tolerability reaction. No severe injection-site reactions were reported and none led to discontinuation of treatment. - A total of 201 SJIA patients aged 2 to less than 20 years have received ILARIS in clinical trials. The safety of ILARIS compared to placebo was investigated in two phase 3 studies. Patients in SJIA Study 1 received a single dose of ILARIS 4 mg/kg (n=43) or placebo (n=41) via subcutaneous injection and were assessed at Day 15 for the efficacy endpoints and had a safety analysis up to Day 29. SJIA Study 2 was a two-part study with an open-label, single-arm active treatment period (Part I) followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design (Part II). Overall, 177 patients were enrolled into the study and received ILARIS 4 mg/kg (up to 300 mg maximum) in Part I, and 100 patients received ILARIS 4 mg/kg (up to 300 mg maximum) every 4 weeks or placebo in Part II. Adverse drug reactions listed in Table 2 showed higher rates than placebo from both trials. The adverse drug reactions associated with ILARIS treatment in SJIA patients were infections, abdominal pain, and injection site reactions. Serious infections (e.g., pneumonia, varicella, gastroenteritis, measles, sepsis, otitis media, sinusitis, adenovirus, lymph node abscess, pharyngitis) were observed in approximately 4% to 5% (0.02 to 0.17 per 100 patient-days) of patients receiving ILARIS in both studies. - Adverse reactions are listed according to MedDRA version 15.0 system organ class. - During clinical trials, no anaphylactic reactions have been reported. In CAPS trials one patient discontinued and in SJIA trials no patients discontinued due to hypersensitivity reactions. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS. - A biosensor binding assay or a bridging immunoassay was used to detect antibodies directed against canakinumab in patients who received ILARIS. Antibodies against ILARIS were observed in approximately 1.5% and 3.1% of the patients treated with ILARIS for CAPS and SJIA, respectively. No neutralizing antibodies were detected. No apparent correlation of antibody development to clinical response or adverse events was observed. The CAPS clinical studies employed the biosensor binding assay, and most of the SJIA clinical studies employed the bridging assay. The data obtained in an assay are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, underlying disease, and the number of patients tested. For these reasons, comparison of the incidence of antibodies to canakinumab between the CAPS and SJIA clinical studies or with the incidence of antibodies to other products may be misleading. - During clinical trials with ILARIS, mean values decreased for white blood cells, neutrophils and platelets. - In the randomized, placebo-controlled portion of SJIA Study 2 decreased white blood cell counts (WBC) less than or equal to 0.8 times lower limit of normal (LLN) were reported in 5 patients (10.4%)in the ILARIS group compared to 2 (4.0%) in the placebo group. Transient decreases in absolute neutrophil count (ANC) to less than 1x109/L were reported in 3 patients (6.0%) in the ILARIS group compared to1 patient (2.0%) in the placebo group. One case of ANC less than 0.5x109/L was observed in the ILARIS group and none in the placebo group. - Mild (less than LLN and greater than 75x109/L) and transient decreases in platelet counts were observed in 3 (6.3%) ILARIS treated patients versus 1 (2.0%) placebo-treated patient. - Elevations of transaminases have been observed in patients treated with ILARIS. - In the randomized, placebo-controlled portion of SJIA Study 2, high ALT and/or AST greater than or equal to 3 times upper limit of normal (ULN) were reported in 2 (4.1%) ILARIS-treated patients and 1 (2.0%) placebo patient. All patients had normal values at the next visit. - Asymptomatic and mild elevations of serum bilirubin have been observed in patients treated with ILARIS without concomitant elevations of transaminases. ## Postmarketing Experience There is limited information regarding Canakinumab Postmarketing Experience in the drug label. # Drug Interactions - Interactions between ILARIS and other medicinal products have not been investigated in formal studies. - An increased incidence of serious infections and an increased risk of neutropenia have been associated with administration of another IL-1 blocker in combination with TNF inhibitors in another patient population. Use of ILARIS with TNF inhibitors may also result in similar toxicities and is not recommended because this may increase the risk of serious infections. - The concomitant administration of ILARIS with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacological interactions between ILARIS and a recombinant IL-1ra, concomitant administration of ILARIS and other agents that block IL-1 or its receptors is not recommended. - No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving ILARIS. Therefore, live vaccines should not be given concurrently with ILARIS. It is recommended that, if possible, pediatric and adult patients should complete all immunizations in accordance with current immunization guidelines prior to initiating ILARIS therapy. - The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as canakinumab, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of canakinumab, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed and the individual dose of the medicinal product may need to be adjusted as needed. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Canakinumab has been shown to produce delays in fetal skeletal development when evaluated in marmoset monkeys using doses 11-fold the maximum recommended human dose (MRHD) and greater (based on a plasma area under the time-concentration curve [AUC] comparison). Doses producing exposures within the clinical exposure range at the MRHD were not evaluated. Similar delays in fetal skeletal development were observed in mice administered a murine analog of canakinumab. There are no adequate and well-controlled studies of ILARIS 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. - Embryofetal developmental toxicity studies were performed in marmoset monkeys and mice. Pregnant marmoset monkeys were administered canakinumab subcutaneously twice-weekly at doses of 15, 50, or 150 mg/kg (representing 11- to 110-fold the human dose based on a plasma AUC comparison at the MRHD) from gestation days 25 to 109 which revealed no evidence of embryotoxicity or fetal malformations. There were increases in the incidence of incomplete ossification of the terminal caudal vertebra and misaligned and/or bipartite vertebra in fetuses at all dose levels when compared to concurrent controls suggestive of delay in skeletal development in the marmoset. Since canakinumab does not cross-react with mouse or rat IL-1, pregnant mice were subcutaneously administered a murine analog of canakinumab at doses of 15, 50, or 150 mg/kg on gestation days 6, 11, and 17. The incidence of incomplete ossification of the parietal and frontal skull bones of fetuses was increased in a dose-dependent manner at all dose levels tested. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Canakinumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Canakinumab during labor and delivery. ### Nursing Mothers - It is not known whether canakinumab is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ILARIS is administered to a nursing woman. ### Pediatric Use - The CAPS trials with ILARIS included a total of 23 pediatric patients with an age range from 4 years to 17 years (11 adolescents were treated subcutaneously with 150 mg , and 12 children were treated with 2 mg/kg based on body weight greater than or equal to 15 kg and less than or equal to 40 kg). The majority of patients achieved improvement in clinical symptoms and objective markers of inflammation (e.g., Serum Amyloid A and C-Reactive Protein). Overall, the efficacy and safety of ILARIS in pediatric and adult patients were comparable. Infections of the upper respiratory tract were the most frequently reported infection. The safety and effectiveness of ILARIS in CAPS patients under 4 years of age has not been established ### Geriatic Use - Clinical studies of ILARIS did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Canakinumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Canakinumab with respect to specific racial populations. ### Renal Impairment No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with renal impairment. ### Hepatic Impairment No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Canakinumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Canakinumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Canakinumab in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Canakinumab in the drug label. # Overdosage - No confirmed case of overdose has been reported. In the case of overdose, it is recommended that the subject be monitored for any signs and symptoms of adverse reactions or effects, and appropriate symptomatic treatment be instituted immediately. # Pharmacology ## Mechanism of Action - Canakinumab is a human monoclonal anti-human IL-1β antibody of the IgG1/κ isotype. Canakinumab binds to human IL-1β and neutralizes its activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). - CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Auto-inflammatory Syndrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis. The NLRP-3 gene encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation. Systemic juvenile idiopathic arthritis (SJIA) is a severe autoinflammatory disease, driven by innate immunity by means of pro-inflammatory cytokines such as interleukin 1β (IL-1β). ## Structure - Canakinumab is a recombinant, human anti-human-IL-1β monoclonal antibody that belongs to the IgG1/κ isotype subclass. It is expressed in a murine Sp2/0-Ag14 cell line and comprised of two 447- (or 448-) residue heavy chains and two 214-residue light chains, with a molecular mass of 145157 Daltons when deglycosylated. Both heavy chains of canakinumab contain oligosaccharide chains linked to the protein backbone at asparagine 298 (Asn 298). - The biological activity of canakinumab is measured by comparing its inhibition of IL-1β-dependent expression of the reporter gene luciferase to that of a canakinumab internal reference standard, using a stably transfected cell line. - ILARIS is supplied in a sterile, single-use, colorless, 6 mL glass vial with coated stopper and aluminum flip-off cap. Each vial contains 180 mg of canakinumab as a white, preservative-free, lyophilized powder. Reconstitution with 1 mL of preservative-free Sterile Water for Injection is required prior to subcutaneous administration of the drug. The reconstituted canakinumab is a 150 mg/mL solution essentially free of particulates, clear to slightly opalescent, and is colorless or may have a slightly brownish-yellow tint. A volume of up to 1 mL can be withdrawn for delivery of 150 mg/mL canakinumab for subcutaneous administration. Each reconstituted vial contains 180 mg canakinumab, sucrose, L-histidine, L-histidine HCL monohydrate, polysorbate 80 and Sterile Water for Injection. No preservatives are present. ## Pharmacodynamics - C-reactive protein and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Following ILARIS treatment, CRP and SAA levels normalize within 8 days. In SJIA the median percent reduction in CRP from baseline to Day 15 was 91%. Improvement in pharmacodynamic markers may not be representative of clinical response. ## Pharmacokinetics - The peak serum canakinumab concentration (Cmax) of 16 ± 3.5 mcg/mL occurred approximately 7 days after subcutaneous administration of a single, 150 mg dose subcutaneously to adult CAPS patients. The mean terminal half-life was 26 days. The absolute bioavailability of subcutaneous canakinumab was estimated to be 66%. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 0.30 to 10 mg/kg given as intravenous infusion or from 150 to 300 mg as subcutaneous injection. - Canakinumab binds to serum IL-1β. Canakinumab volume of distribution (Vss) varied according to body weight and was estimated to be 6.01 liters in a typical CAPS patient weighing 70 kg, and 3.2 liters in a SJIA patient weighing 33 kg. The expected accumulation ratio was 1.3-fold for CAPS patients and 1.6-fold for SJIA patients following 6 months of subcutaneous dosing of 150 mg ILARIS every 8 weeks and 4 mg/kg every 4 weeks, respectively. - Clearance (CL) of canakinumab varied according to body weight and was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg and 0.11 L/day in a SJIA patient weighing 33 kg. There was no indication of accelerated clearance or time-dependent change in the pharmacokinetic properties of canakinumab following repeated administration. No gender- or age-related pharmacokinetic differences were observed after correction for body weight. - Pharmacokinetic properties are similar in CAPS and SJIA pediatric populations. - In CAPS patients, peak concentrations of canakinumab occurred between 2 to 7 days following single subcutaneous administration of ILARIS 150 mg or 2 mg/kg in pediatric patients. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokinetic properties observed in adults. - In SJIA, exposure parameters (such as AUC and Cmax) were comparable across age groups from 2 years of age and above following subcutaneous administration of canakinumab 4 mg/kg every 4 weeks. ## Nonclinical Toxicology - Long-term animal studies have not been performed to evaluate the carcinogenic potential of canakinumab. - The mutagenic potential of canakinumab was not evaluated. - As canakinumab does not cross-react with rodent IL-1β, male and female fertility was evaluated in a mouse model using a murine analog of canakinumab. Male mice were treated weekly beginning 4 weeks prior to mating and continuing through 3 weeks after mating. Female mice were treated weekly for 2 weeks prior to mating through gestation day 3 or 4. The murine analog of canakinumab did not alter either male or female fertility parameters at subcutaneous doses up to 150 mg/kg. # Clinical Studies - The efficacy and safety of ILARIS for the treatment of CAPS was demonstrated in CAPS Study 1, a 3-part trial in patients 9 to 74 years of age with the MWS phenotype of CAPS. Throughout the trial, patients weighing more than 40 kg received ILARIS 150 mg and patients weighing 15 to 40 kg received 2 mg/kg. Part 1 was an 8-week open-label, single-dose period where all patients received ILARIS. Patients who achieved a complete clinical response and did not relapse by Week 8 were randomized into Part 2, a 24-week randomized, double-blind, placebo-controlled withdrawal period. Patients who completed Part 2 or experienced a disease flare entered Part 3, a 16-week open-label active treatment phase. A complete response was defined as ratings of minimal or better for physician’s assessment of disease activity (PHY) and assessment of skin disease (SKD) and had serum levels of C-Reactive Protein (CRP) and Serum Amyloid A (SAA) less than 10 mg/L. A disease flare was defined as a CRP and/or SAA values greater than 30 mg/L and either a score of mild or worse for PHY or a score of minimal or worse for PHY and SKD. - In Part 1, a complete clinical response was observed in 71% of patients one week following initiation of treatment and in 97% of patients by Week 8 (see Figure 1 and Table 3). In the randomized withdrawal period, a total of 81% of the patients randomized to placebo flared as compared to none (0%) of the patients randomized to ILARIS. The 95% confidence interval for treatment difference in the proportion of flares was 53% to 96%. At the end of Part 2, all 15 patients treated with ILARIS had absent or minimal disease activity and skin disease (see Table 3). - In a second trial, patients 4 to 74 years of age with both MWS and FCAS phenotypes of CAPS were treated in an open-label manner. Treatment with ILARIS resulted in clinically significant improvement of signs and symptoms and in normalization of high CRP and SAA in a majority of patients within 1 week. - The efficacy of ILARIS for the treatment of active SJIA was assessed in 2 phase 3 studies (SJIA Study 1 and SJIA Study 2). Patients enrolled were aged 2 to less than 20 years (mean age at baseline: 8.5 years) with a confirmed diagnosis of SJIA at least 2 months before enrollment (mean disease duration at baseline: 3.5 years). Patients had active disease defined as greater than or equal to 2 joints with active arthritis (mean number of active joints at baseline: 15.4), documented spiking, intermittent fever (body temperature greater than 38°C) for at least 1 day within 1 week before study drug administration, and CRP greater than 30 mg/L (normal range less than 10 mg/L)(mean CRP at baseline: 200.5 mg/L). Patients were allowed to continue their stable dose of methotrexate, corticosteroids, and/or NSAIDs without change, except for tapering of the corticosteroid dose as per study design in SJIA Study 2 (see below). - SJIA Study 1 was a randomized, double-blind, placebo-controlled, single-dose 4-week study assessing the short term efficacy of ILARIS in 84 patients randomized to receive a single subcutaneous dose of 4 mg/kg ILARIS or placebo (43 patients received ILARIS and 41 patients received placebo). The primary objective of this study was to demonstrate the superiority of ILARIS versus placebo in the proportion of patients who achieved at least 30% improvement in an adapted pediatric American College of Rheumatology (ACR) response criterion which included both the pediatric ACR core set (ACR30 response) and absence of fever (temperature less than or equal to 38°C in the preceding 7 days) at Day 15. - Pediatric ACR responses are defined by achieving levels of percentage improvement (30%, 50%, and 70%) from baseline in at least 3 of the 6 core outcome variables, with worsening of greater than or equal to 30% in no more than one of the remaining variables. Core outcome variables included a physician global assessment of disease activity, parent or patient global assessment of wellbeing, number of joints with active arthritis, number of joints with limited range of motion, CRP, and functional ability (Childhood Health Assessment Questionnaire-CHAQ). - Percentages of patients by pediatric ACR response are presented in Table 4. - Results for the components of the pediatric ACR core set were consistent with the overall ACR response results, for systemic and arthritic components including the reduction in the total number of active joints and joints with limited range of motion. Among the patients who returned for a Day 15 visit, the mean change in patient pain score (0 to 100 mm visual analogue scale) was -50.0 mm on ILARIS (N=43), as compared to +4.5 mm on placebo (N=25). The mean change in pain score among ILARIS treated patients was consistent through Day 29. All patients treated with ILARIS had no fever at Day 3 compared to 87% of patients treated with placebo. - SJIA Study 2 was a randomized, double-blind, placebo-controlled, withdrawal study of flare prevention by ILARIS in patients with active SJIA. Flare was defined by worsening of greater than or equal to 30% in at least 3 of the 6 core Pediatric ACR response variables combined with improvement of greater than or equal to 30% in no more than 1 of the 6 variables, or reappearance of fever not due to infection for at least 2 consecutive days. The study consisted of 2 major parts. One hundred seventy-seven patients were enrolled in the study and received 4 mg/kg ILARIS subcutaneously every 4 weeks in Part I and 100 of these patients continued into Part II to receive either ILARIS 4 mg/kg or placebo subcutaneously every 4 weeks. - Of the total 128 patients who entered the open-label portion of Study 2 taking corticosteroids, 92 attempted corticosteroid tapering. Fifty-seven (62%) of the 92 patients who attempted to taper were able to successfully taper their corticosteroid dose and 42 (46%) discontinued corticosteroids. - Time to Flare - Part II was a randomized withdrawal design to demonstrate that the time to flare was longer with ILARIS than with placebo. Follow-up stopped when 37 events had been observed resulting in patients being followed for different lengths of time. The probability of experiencing a flare over time in Part II was statistically lower for the ILARIS treatment group than for the placebo group (Figure 2). This corresponded to a 64% relative reduction in the risk of flare for patients in the ILARIS group as compared to those in the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75). # How Supplied - Carton of 1 vial………………………………………………………………………………………….NDC 0078-0582-61 - Each single-use vial of ILARIS contains a sterile, preservative free, white lyophilized powder containing 180 mg of canakinumab. Each vial is to be reconstituted with 1 mL of preservative-free Sterile Water for Injection resulting in a final concentration of 150 mg/mL. ## Storage - The unopened vial must be stored refrigerated at 2°C to 8°C (36°F to 46° F). Do not freeze. Store in the original carton to protect from light. Do not use beyond the date stamped on the label. After reconstitution, ILARIS should be kept from light, and can be kept at room temperature if used within 60 minutes of reconstitution. Otherwise, it should be refrigerated at 2°C to 8°C (36°F to 46°F) and used within 4 hours of reconstitution. ILARIS does not contain preservatives. Unused portions of ILARIS should be discarded. - Keep this and all drugs out of the reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be advised of the potential benefits and risks of ILARIS. Physicians should instruct their patients to read the Medication Guide before starting ILARIS therapy. - Patients should be advised that healthcare providers should perform administration of ILARIS, by the subcutaneous injection route. - Patients should be cautioned that ILARIS use has been associated with serious infections. Patients should be counseled to contact their healthcare professional immediately if they develop an infection after starting ILARIS. Treatment with ILARIS should be discontinued if a patient develops a serious infection. Patients should be counseled not to take any IL-1 blocking drug, including ILARIS, if they are also taking a drug that blocks TNF such as etanercept, infliximab, or adalimumab. Use of ILARIS with other IL-1 blocking agents, such as rilonacept and anakinra is not recommended. Patients should be cautioned not to receive ILARIS if they have a chronic or active infection, including HIV, Hepatitis B or Hepatitis C. - Prior to initiation of therapy with ILARIS, physicians should review with adult and pediatric patients their vaccination history relative to current medical guidelines for vaccine use, including taking into account the potential of increased risk of infection during treatment with ILARIS. - Physicians should explain to patients that a very small number of patients in the clinical trials experienced a reaction at the subcutaneous injection site. Injection-site reactions may include pain, erythema, swelling, pruritus, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Healthcare providers should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician. - Patients should be counseled to contact their healthcare provider immediately if they develop signs of allergic reaction such as difficulty breathing or swallowing, nausea, dizziness, skin rash, itching, hives, palpitations or low blood pressure. # Precautions with Alcohol - Alcohol-Canakinumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ILARIS®[1] # Look-Alike Drug Names There is limited information regarding Canakinumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Canakinumab
7438a7e78d1520de9152ff48372aa62e9e268120	wikidoc	Ylang-ylang	Ylang-ylang Ylang-ylang (Template:IPA2) (ee-lahng ee-lahng) Cananga odorata, is a small flower of the cananga tree. It is a fast-growing tree that exceeds 5 meters per year and attains an average height of 12 meters. It grows in full or partial sun, and prefers the acidic soils of its native rainforest habitat. The leaves are long, smooth and glossy. The flower is greenish yellow (rarely pink), curly like a starfish, and yields a highly fragrant essential oil. A related species is Cananga fruticosa, which is a dwarf ylang-ylang that grows as small tree or compact shrub with highly scented flowers. Ylang-ylang has been cultivated in temperate climates under conservatory conditions. Its fruit are an important food item for birds, such as the Collared Imperial-pigeon, Purple-tailed Imperial-pigeon, Zoe's Imperial-pigeon, Superb Fruit-dove, Pink-spotted Fruit-dove, Coroneted Fruit-dove, Orange-bellied Fruit-dove, and Wompoo Fruit-dove (Frith et al. 1976). The name ylang-ylang is derived from Tagalog, either from the word ilang, meaning "wilderness", alluding to its natural habitat, or the word ilang-ilan, meaning "rare", suggestive of its exceptionally delicate scent. The plant is native to the Philippines and Indonesia and is commonly grown in Polynesia, Melanesia and Micronesia. The fragrance of ylang-ylang is rich and deep with notes of rubber and custard, and bright with hints of jasmine and neroli. The essential oil of the flower is obtained through steam distillation of the flowers and separated into different grades (extra; 1; 2; 3) according to when the distillates are obtained. The main aromatic component of ylang-ylang is methyl anthranilate. The essential oil of ylang-ylang is used in aromatherapy. It is believed to relieve high blood pressure, normalize sebum secretion for skin problems, and is considered to be an aphrodisiac. According to Margaret Mead, it was used as such by South Pacific natives such as the Solomons where she did much of her research. The oil from ylang-ylang is widely used in perfumery for oriental or floral themed perfumes. Ylang-ylang blends well with most floral, fruit and wood smells. In Indonesia, ylang-ylang flowers are spread on the bed of newlywed couples. In the Philippines, its flowers, together with the flowers of the sampaguita, are strung into a necklace and worn by women and used to adorn religious images. Ylang-ylang's essential oil makes up 29% of the Comoros' annual export (1998). # Notes - ↑ Manner, Harley and Craig Elevitch,Traditional Tree Initiative: Species Profiles for Pacific Island Agroforestry (2006), Permanent Agricultural Resources, Honolulu, Hi. - ↑ The Perfume Tree Ylang-Ylang	Ylang-ylang Ylang-ylang (Template:IPA2) (ee-lahng ee-lahng) Cananga odorata, is a small flower of the cananga tree. It is a fast-growing tree that exceeds 5 meters per year and attains an average height of 12 meters. It grows in full or partial sun, and prefers the acidic soils of its native rainforest habitat. The leaves are long, smooth and glossy. The flower is greenish yellow (rarely pink), curly like a starfish, and yields a highly fragrant essential oil. A related species is Cananga fruticosa, which is a dwarf ylang-ylang that grows as small tree or compact shrub with highly scented flowers. Ylang-ylang has been cultivated in temperate climates under conservatory conditions. Its fruit are an important food item for birds, such as the Collared Imperial-pigeon, Purple-tailed Imperial-pigeon, Zoe's Imperial-pigeon, Superb Fruit-dove, Pink-spotted Fruit-dove, Coroneted Fruit-dove, Orange-bellied Fruit-dove, and Wompoo Fruit-dove (Frith et al. 1976). The name ylang-ylang is derived from Tagalog, either from the word ilang, meaning "wilderness", alluding to its natural habitat, or the word ilang-ilan, meaning "rare", suggestive of its exceptionally delicate scent. The plant is native to the Philippines and Indonesia and is commonly grown in Polynesia, Melanesia and Micronesia. The fragrance of ylang-ylang is rich and deep with notes of rubber and custard, and bright with hints of jasmine and neroli. The essential oil of the flower is obtained through steam distillation of the flowers and separated into different grades (extra; 1; 2; 3) according to when the distillates are obtained. The main aromatic component of ylang-ylang is methyl anthranilate.[1] The essential oil of ylang-ylang is used in aromatherapy. It is believed to relieve high blood pressure, normalize sebum secretion for skin problems, and is considered to be an aphrodisiac.[2] According to Margaret Mead, it was used as such by South Pacific natives such as the Solomons where she did much of her research. The oil from ylang-ylang is widely used in perfumery for oriental or floral themed perfumes. Ylang-ylang blends well with most floral, fruit and wood smells. In Indonesia, ylang-ylang flowers are spread on the bed of newlywed couples. In the Philippines, its flowers, together with the flowers of the sampaguita, are strung into a necklace and worn by women and used to adorn religious images. Ylang-ylang's essential oil makes up 29% of the Comoros' annual export (1998). # Notes - ↑ Manner, Harley and Craig Elevitch,Traditional Tree Initiative: Species Profiles for Pacific Island Agroforestry (2006), Permanent Agricultural Resources, Honolulu, Hi. - ↑ The Perfume Tree Ylang-Ylang	https://www.wikidoc.org/index.php/Cananga_Oil
9b739f2f5eec2d26350c67a2a9911765769a2993	wikidoc	Candesartan	Candesartan # 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 Candesartan is an angiotensin II receptor blocker that is FDA approved for the {{{indicationType}}} of hypertension and heart failure. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, backache, dizziness, pharyngitis, rhinitis and upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Starting dosage: - 16 mg/day, as monotherapy, in non-volume depleted patients. - Use in hepatic impairment: - Initiate with 8 mg/day. If blood pressure is not controlled by candesartan cilexetil alone, a diuretic may be added. - Candesartan cilexetil may be administered with other antihypertensive agents. - Initial dosage: - 4 mg/day - Target dosage, achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient: - 32 mg/day ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of candesartan cilexetil in adult patients. ### Non–Guideline-Supported Use - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - 1 to < 17 Years of age Candesartan cilexetil may be administered once daily or divided into two equal doses. - In children 1 - 6 years of age: - Initial dosage: - 0.20 mg/kg/day PO - Further dosages: - 0.05 to 0.4 mg/kg per day PO - Children 6 - 17 years of age: - Less than 50 kg - Initial dosage: - 4 to 8 mg/day PO - Further dosages: - 2 to 16 mg per day PO - Greater than 50 kg - Initial dosage: - 8 to 16 mg/day PO - Further dosages: - 4 to 32 mg/day PO - For patients who can not swallow a pill, follow the instructions below for preparation of the suspension. The number of tablets and volume of vehicle specified below will yield 160 mL of a 1 mg/mL suspension: - Prepare the vehicle by adding equal volumes of 1Ora-Plus® (80 mL) and 1Ora-Sweet SF® (80 mL) or, alternatively, use, 1,2Ora-Blend SF® (160 mL). - Add a small amount of vehicle to the required number of ATACAND tablets (five 32 mg tablets) and grind into a smooth paste using a mortar and pestle. - Add the paste to a preparation vessel of suitable size. - Rinse the mortar and pestle clean using the vehicle and add this to the vessel. Repeat, if necessary. - Prepare the final volume by adding the remaining vehicle. - Mix thoroughly. - Dispense into suitably sized amber PET bottles. - Label with an expiry date of 100 days and include the following instructions: - Store at room temperature (below 30°C/86°F). Use within 30 days after first opening. Do not use after the expiry date stated on the bottle. - Do not freeze. - Shake well before each use. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of candesartan cilexetil in children. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non-Guideline-Supported Use of candesartan cilexetil in adult patients. # Contraindications - Hypersensitivity to candesartan. - Do not co-administer aliskiren with candesartan cilexetil in diabetic patients. # 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 - Death - When pregnancy is detected, discontinue candesartan cilexetil as soon as possible. - Oral doses ≥10 mg of candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. The 10-mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32 mg on a mg/m2 basis (comparison assumes human body weight of 50 kg). - Candesartan cilexetil given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m2 basis) caused maternal toxicity (decreased body weight and death) but, in surviving dams, had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development. - No maternal toxicity or adverse effects on fetal development were observed when oral doses up to 1000 mg of candesartan cilexetil/kg/day (approximately 138 times the MRHD on a mg/m2 basis) were administered to pregnant mice. - Children < 1 year of age must not receive candesartan cilexetil for hypertension. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys. - Candesartan cilexetil can cause symptomatic hypotension. - 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. - Patients with symptomatic hypotension may require temporarily reducing the dose of candesartan cilexetil, diuretic or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with candesartan cilexetil. - In the CHARM program (heart failure patients), hypotension was reported in 18.8% of patients on candesartan cilexetil versus 9.8% of patients on placebo. The incidence of hypotension leading to drug discontinuation in candesartan cilexetil-treated patients was 4.1% compared with 2.0% in placebo-treated patients. In the CHARM-Added program, where candesartan or placebo was given in addition to ACE inhibitors, hypotension was reported in 22.6% of patients treated with candesartan cilexetil versus 13.8% treated with placebo. - Monitoring of blood pressure is recommended during dose escalation and periodically thereafter. - Major Surgery/Anesthesia - Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists, including candesartan cilexetil, due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors. - Monitor renal function periodically in patients treated with candesartan cilexetil. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend, in part, on the activity of the renin-angiotensin system (e.g., patient with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia or acute renal failure when treated with candesartan cilexetil. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil. - In the CHARM program (heart failure patients), the incidence of abnormal renal function (e.g., creatinine increase) was 12.5% in patients treated with candesartan cilexetil versus 6.3% in patients treated with placebo. The incidence of abnormal renal function (e.g., creatinine increase) leading to drug discontinuation in candesartan cilexetil-treated patients was 6.3% compared with 2.9% in placebo-treated patients. In the CHARM-Added program, where candesartan or placebo was given in addition to ACE inhibitors, the incidence of abnormal renal function (e.g., creatinine increase) was 15% in patients treated with candesartan cilexetil versus 9% in patients treated with placebo. - Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. - Monitor serum potassium periodically. - In the CHARM program (heart failure patients), the incidence of hyperkalemia was 6.3% in patients treated with candesartan cilexetil versus 2.1% in patients treated with placebo. The incidence of hyperkalemia leading to drug discontinuation in candesartan cilexetil-treated patients was 2.4% compared with 0.6% in placebo-treated patients. In the CHARM-Added program where candesartan or placebo was given in addition to ACE inhibitors, the incidence of hyperkalemia was 9.5% in patients treated with candesartan cilexetil versus 3.5% in patients treated with placebo. # Adverse Reactions ## Clinical Trials Experience - Adult Hypertension: - 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. - Candesartan cilexetil has been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied for at least 6 months and about 200 for at least 1 year. In general, treatment with candesartan cilexetil was well tolerated. The overall incidence of adverse events reported with candesartan cilexetil was similar to placebo. - The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (ie, 108 of 3260) of patients treated with candesartan cilexetil as monotherapy and 3.5% (ie, 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (ie, 57 of 2350) of patients treated with candesartan cilexetil and 3.4% (ie, 35 of 1027) of patients treated with placebo. - Pediatric hypertension - Among children in clinical studies, 1 in 93 children age 1 to < 6 and 3 in 240 age 6 to < 17 experienced worsening renal disease. The association between candesartan and exacerbation of the underlying condition could not be excluded. - Heart failure - The adverse event profile of candesartan cilexetil in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing candesartan cilexetil in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued candesartan cilexetil for adverse events vs. 16.1% of placebo patients. - Headache - Dizziness - Heart Failure - Upper respiratory tract infection - Pharyngitis - Rhinitis - Back pain ## Postmarketing Experience - The following adverse reactions were identified during post-approval use of candesartan cilexetil. 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. - Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. The following have been very rarely reported in post-marketing experience: - Abnormal hepatic function - Hepatitis - Neutropenia - Leukopenia - Agranulocytosis - Angioedema - Hyperkalemia - Hyponatremia - Cough - Pruritus - Rash - Urticaria # Drug Interactions - Lithium - NSAIDS - Dual inhibition of the renin-angiotensin system - Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, and with some angiotensin II receptor antagonists. - An increase in serum lithium concentration has been reported during concomitant administration of lithium with candesartan cilexetil. - Monitor serum lithium levels. - Including Selective Cyclooxygenase-2 Inhibitors (COX-2 inhibitors). - In elderly patients, 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 candesartan, may result in deterioration of renal function, including possible acute renal failure. - These effects are usually reversible. - Monitor renal function periodically in patients receiving candesartan and NSAID therapy. - The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors. - 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 candesartan cilexetil and other agents that affect the RAS. - Do not co-administer aliskiren with candesartan celexetil in patients with diabetes. - Avoid use of aliskiren with candesartan celexetil 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 - Death - When pregnancy is detected, discontinue candesartan celexetil as soon as possible. - These adverse outcomes are usually associated with use of similar drugs in the second and third trimester of pregnancy. - Most epidemiological 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 candesartan celexetil, 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 candesartan celexetil for hypotension, oliguria, and hyperkalemia. Pregnancy Category (AUS): D There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of candesartan celexetil in women who are pregnant. ### Labor and Delivery The effect of candesartan celexetil on labor and delivery in humans is unknown. ### Nursing Mothers - It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be present in rat milk. - Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue candesartan celexetil, taking into account the importance of the drug to the mother. ### Pediatric Use - Neonates with a history of in utero exposure to candesartan celexetil: - 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 candesartan celexetil were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies. The pharmacokinetics of candesartan celexetil have been evaluated in pediatric patients 1 to < 17 years of age. - Children < 1 year of age must not receive candesartan celexetil for hypertension. ### Geriatic Use There is no FDA guidance on the use of Candesartan in geriatric settings. ### Gender There is no FDA guidance on the use of Candesartan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Candesartan with respect to specific racial populations. ### Renal Impairment - In hypertensive patients with renal insufficiency, serum concentrations of candesartan are elevated. - After repeated dosing, the AUC and Cmax were noted to be approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m2) compared to patients with normal kidney function. - The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. - Candesartan cannot be removed by hemodialysis. - No initial dosage adjustment is necessary in patients with renal insufficiency. - In heart failure patients with renal impairment, AUC0-72h was noted to be 36% and 65% higher in mild and moderate renal impairment, respectively. Cmax was 15% and 55% higher in mild and moderate renal impairment, respectively. ### Hepatic Impairment - The pharmacokinetics of candesartan were compared in patients with mild and moderate hepatic impairment to matched healthy volunteers following a single oral dose of 16 mg candesartan cilexetil. - The increase in AUC for candesartan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in Cmax for candesartan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. - The pharmacokinetics after candesartan cilexetil administration have not been investigated in patients with severe hepatic impairment. No initial dosage adjustment is necessary in patients with mild hepatic impairment. In hypertensive patients with moderate hepatic impairment, consideration should be given to initiation of candesartan at a lower dose ### Females of Reproductive Potential and Males - There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg). - Candesartan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. - Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. - Candesartan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results. Candesartan cilexetil was not evaluated in the CHL chromosomal aberration or CHO gene mutation assay. - Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of up to 300 mg/kg/day (83 times the maximum daily human dose of 32 mg on a body surface area basis). ### Immunocompromised Patients There is no FDA guidance one the use of Candesartan in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - 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 - Death - When pregnancy is detected, discontinue candesartan cilexetil as soon as possible. - Children < 1 year of age must not receive candesartan cilexetil for hypertension. - Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys. - Candesartan cilexetil can cause symptomatic hypotension. - 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. - Patients with symptomatic hypotension may require temporarily reducing the dose of candesartan cilexetil, diuretic or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with candesartan cilexetil. - Monitoring of blood pressure is recommended during dose escalation and periodically thereafter. - Monitor renal function periodically in patients treated with candesartan cilexetil. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend, in part, on the activity of the renin-angiotensin system (e.g., patient with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia or acute renal failure when treated with candesartan cilexetil. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil. - Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. - Monitor serum potassium periodically. # IV Compatibility There is limited information regarding the compatibility of candesartan cilexetil and IV administrations. # Overdosage - No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. - The most likely manifestation of overdosage with candesartan cilexetil would be: - Hypotension - Dizziness - Tachycardia - Bradycardia, could occur from parasympathetic (vagal) stimulation. - If symptomatic hypotension should occur, supportive treatment should be instituted. - Candesartan cannot be removed by hemodialysis. - Treatment: To obtain up-to-date information about the treatment of overdose, consult your 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 overdoses, drug-drug interactions, and altered pharmacokinetics in your patient. # Pharmacology ## Mechanism of Action - Angiotensin II is 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, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. - Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis. - There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. - Candesartan has much greater affinity (>10,000-fold) for the AT1 receptor than for the AT2 receptor. - Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. - ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. - Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. - Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure. ## Structure - Candesartan cilexetil, a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract. - Candesartan is a selective AT1 subtype angiotensin II receptor antagonist. - Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1--7-benzimidazolecarboxylate, cyclohexyl carbonate (ester). Its empirical formula is C33H34N6O6, and its structural formula is: - Candesartan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral. ## Pharmacodynamics - Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. - After 1 week of once daily dosing with 8 mg of candesartan cilexetil, the pressor effect was inhibited by approximately 90% at peak with approximately 50% inhibition persisting for 24 hours. - Plasma concentrations of angiotensin I and angiotensin II, and plasma renin activity (PRA), increased in a dose-dependent manner after single and repeated administration of candesartan cilexetil to healthy subjects, hypertensive, and heart failure patients. - ACE activity was not altered in healthy subjects after repeated candesartan cilexetil administration. The once-daily administration of up to 16 mg of candesartan cilexetil to healthy subjects did not influence plasma aldosterone concentrations, but a decrease in the plasma concentration of aldosterone was observed when 32 mg of candesartan cilexetil was administered to hypertensive patients. In spite of the effect of candesartan cilexetil on aldosterone secretion, very little effect on serum potassium was observed. - Hypertension - Adults - In multiple-dose studies with hypertensive patients, there were no clinically significant changes in metabolic function, including serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a 12-week study of 161 patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension, there was no change in the level of HbA1c. - In heart failure patients, candesartan ≥ 8 mg resulted in decreases in systemic vascular resistance and pulmonary capillary wedge pressure. ## Pharmacokinetics - Distribution - The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that candesartan crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus. - Metabolism and Excretion - Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of 14C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of 14C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of candesartan. - Adults - Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT1 subtype angiotensin II receptor antagonist. Candesartan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. The elimination half-life of candesartan is approximately 9 hours. After single and repeated administration, the pharmacokinetics of candesartan are linear for oral doses up to 32 mg of candesartan cilexetil. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing. Following administration of candesartan cilexetil, the absolute bioavailability of candesartan was estimated to be 15%. After tablet ingestion, the peak serum concentration (Cmax) is reached after 3 to 4 hours. Food with a high fat content does not affect the bioavailability of candesartan after candesartan cilexetil administration. - Pediatrics - In children 1 to 17 years of age, plasma levels are greater than 10–fold higher at peak (approximately 4 hours) than 24 hours after a single dose. - Children 1 to < 6 years of age, given 0.2 mg/kg had exposure similar to adults given 8 mg. - Children > 6 years of age had exposure similar to adults given the same dose. - The pharmacokinetics (Cmax and AUC) were not modified by age, sex or body weight. - Candesartan cilexetil pharmacokinetics have not been investigated in pediatric patients less than 1 year of age. - From the dose-ranging studies of candesartan cilexetil, there was a dose related increase in plasma candesartan concentrations. - The renin-angiotensin system (RAS) plays a critical role in kidney development. RAS blockade has been shown to lead to abnormal kidney development in very young mice. Children < 1 year of age must not receive ATACAND. Administering drugs that act directly on the renin-angiotensin system (RAS) can alter normal renal development. - 'Geriatric and Sex - The pharmacokinetics of candesartan have been studied in the elderly (≥ 65 years) and in both sexes. The plasma concentration of candesartan was higher in the elderly (Cmax was approximately 50% higher, and AUC was approximately 80% higher) compared to younger subjects administered the same dose. The pharmacokinetics of candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration. No initial dosage adjustment is necessary. There is no difference in the pharmacokinetics of candesartan between male and female subjects. - Renal Insufficiency - In hypertensive patients with renal insufficiency, serum concentrations of candesartan were elevated. After repeated dosing, the AUC and Cmax were approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m2) compared to patients with normal kidney function. The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. Candesartan cannot be removed by hemodialysis. No initial dosage adjustment is necessary in patients with renal insufficiency . - In heart failure patients with renal impairment, AUC0-72h was 36% and 65% higher in mild and moderate renal impairment, respectively. Cmax was 15% and 55% higher in mild and moderate renal impairment, respectively. - Pediatrics: Candesartran cilexetil pharmacokinetics have not been determined in children with renal insufficiency. - Hepatic Insufficiency - The pharmacokinetics of candesartan were compared in patients with mild and moderate hepatic impairment to matched healthy volunteers following a single oral dose of 16 mg candesartan cilexetil. The increase in AUC for candesartan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in Cmax for candesartan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. The pharmacokinetics after candesartan cilexetil administration have not been investigated in patients with severe hepatic impairment. No initial dosage adjustment is necessary in patients with mild hepatic impairment. In hypertensive patients with moderate hepatic impairment, consideration should be given to initiation of candesartran cilexetil at a lower dose. - Heart Failure - The pharmacokinetics of candesartan were linear in patients with heart failure (NYHA class II and III) after candesartan cilexetil doses of 4, 8, and 16 mg. After repeated dosing, the AUC was approximately doubled in these patients compared with healthy, younger patients. The pharmacokinetics in heart failure patients is similar to that in healthy elderly volunteers. ## Nonclinical Toxicology - There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg). - Candesartan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. - Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. - Candesartan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results. Candesartan cilexetil was not evaluated in the CHL chromosomal aberration or CHO gene mutation assay. - Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of up to 300 mg/kg/day (83 times the maximum daily human dose of 32 mg on a body surface area basis). # Clinical Studies - Adult - The antihypertensive effects of candesartran cilexetil were examined in 14 placebo-controlled trials of 4- to 12-weeks duration, primarily at daily doses of 2 to 32 mg per day in patients with baseline diastolic blood pressures of 95 to 114 mm Hg. Most of the trials were of candesartan cilexetil as a single agent, but it was also studied as add-on to hydrochlorothiazide and amlodipine. These studies included a total of 2350 patients randomized to one of several doses of candesartan cilexetil and 1027 to placebo. Except for a study in diabetics, all studies showed significant effects, generally dose related, of 2 to 32 mg on trough (24 hour) systolic and diastolic pressures compared to placebo, with doses of 8 to 32 mg giving effects of about 8-12/4-8 mm Hg. There were no exaggerated first-dose effects in these patients. Most of the antihypertensive effect was seen within 2 weeks of initial dosing and the full effect in 4 weeks. With once-daily dosing, blood pressure effect was maintained over 24 hours, with trough to peak ratios of blood pressure effect generally over 80%. Candesartan cilexetil had an additional blood pressure lowering effect when added to hydrochlorothiazide. - The antihypertensive effects of candesartan cilexetil and losartan potassium at their highest recommended doses administered once-daily were compared in two randomized, double-blind trials. In a total of 1268 patients with mild to moderate hypertension who were not receiving other antihypertensive therapy, candesartan cilexetil 32 mg lowered systolic and diastolic blood pressure by 2 to 3 mm Hg on average more than losartan potassium 100 mg, when measured at the time of either peak or trough effect. The antihypertensive effects of twice daily dosing of either candesartan cilexetil or losartan potassium were not studied. - The antihypertensive effect was similar in men and women and in patients older and younger than 65. Candesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population). This has been generally true for angiotensin II antagonists and ACE inhibitors. In long-term studies of up to 1 year, the antihypertensive effectiveness of candesartan cilexetil was maintained, and there was no rebound after abrupt withdrawal. - There were no changes in the heart rate of patients treated with candesartan cilexetil in controlled trials. - Pediatric - The antihypertensive effects of candesartran cilexetil were evaluated in hypertensive children 1 to < 6 years old and 6 to < 17 years of age in two randomized, double-blind multicenter, 4-week dose ranging studies. There were 93 patients 1 to < 6 years of age, 74% of whom had renal disease, that were randomized to receive an oral dose of candesartan cilexetil suspension 0.05, 0.20 or 0.40 mg/kg once daily. The primary method of analysis was slope of the change in systolic blood pressure (SBP) as a function of dose. Since there was no placebo group, the change from baseline likely overestimates the true magnitude of blood pressure effect. Nevertheless, SBP and diastolic blood pressure (DBP) decreased 6.0/5.2 to 12.0/11.1 mmHg from baseline across the three doses of candesartan. - In children 6 to 50 kg the candesartran cilexetil doses were 4, 16 or 32 mg once daily. Those enrolled were 47% Black and 29% were female; mean age +/- SD was 12.9 +/- 2.6 years. - The placebo subtracted effect at trough for sitting systolic blood pressure/sitting diastolic blood pressure for the different doses were from 4.9/3.0 to 7.5/6.2 mmHg. In children 6 to < 17 years there was a trend for a lesser blood pressure effect for Blacks compared to other patients. There were too few individuals in the age group of 1 - 6 years old to determine whether Blacks respond differently than other patients to candesartran cilexetil. - Candesartan was studied in two heart failure outcome studies: 1. The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity trial in patients intolerant of ACE inhibitors (CHARM–Alternative), 2. CHARM–Added in patients already receiving ACE inhibitors. Both studies were international double-blind, placebo-controlled trials in patients with NYHA class II - IV heart failure and LVEF ≤40%. In both trials, patients were randomized to placebo or candesartran cilexetil (initially 4-8 mg once daily, titrated as tolerated to 32 mg once daily) and followed for up to 4 years. Patients with serum creatinine > 3 mg/dL, serum potassium > 5.5 mEq/L, symptomatic hypotension or known bilateral renal artery stenosis were excluded. The primary end point in both trials was time to either cardiovascular death or hospitalization for heart failure. - CHARM–Alternative included 2028 subjects not receiving an ACE inhibitor due to intolerance. The mean age was 67 years and 32% were female, 48% were NYHA II, 49% were NYHA III, 4% were NYHA IV, and the mean ejection fraction was 30%. Sixty-two percent had a history of myocardial infarction, 50% had a history of hypertension, and 27% had diabetes. Concomitant drugs at baseline were diuretics (85%), digoxin (46%), beta-blockers (55%), and spironolactone (24%). The mean daily dose of candesartran cilexetil was approximately 23 mg and 59% of subjects on treatment received 32 mg once daily. - After a median follow-up of 34 months, there was a 23% reduction in the risk of cardiovascular death or heart failure hospitalization on candesartran cilexetil (p<0.001), with both components contributing to the overall effect (Table 1). - In CHARM–Added, 2548 subjects receiving an ACE inhibitor were randomized to candesartran cilexetil or placebo. The specific ACE inhibitor and dose were at the discretion of the investigators, who were encouraged to titrate patients to doses known to be effective in clinical outcome trials, subject to patient tolerability. Forced titration to maximum tolerated doses of ACE inhibitor was not required. - The mean age was 64 years and 21% were female, 24% were NYHA II, 73% were NYHA III, 3% were NYHA IV, and the mean ejection fraction was 28%. Fifty-six percent had a history of myocardial infarction, 48% had a history of hypertension, and 30% had diabetes. Concomitant drugs at baseline in addition to ACE inhibitors were diuretics (90%), digoxin (58%), beta-blockers (55%), and spironolactone (17%). The mean daily dose of candesartran cilexetil was approximately 24 mg and 61% of subjects on treatment received 32 mg once daily. After a median follow-up of 41 months, there was a 15% reduction in the risk of cardiovascular death or heart failure hospitalization on candesartran cilexetil (p=0.011), with both components contributing to the overall effect (Table 2). There was no evident relationship between dose of ACE inhibitor and the benefit of candesartran cilexetil. - In these two studies, the benefit of candesartran cilexetil in reducing the risk of CV death or heart failure hospitalization (18% p<0.001) was evident in major subgroups (see Figure), and in patients on other combinations of cardiovascular and heart failure treatments, including ACE inhibitors and beta-blockers. CV Death or Heart Failure Hospitalization in Subgroups – LV Systolic Dysfunction Trials # How Supplied - No. 3782 — Tablets candesartan cilexetil, 4 mg, are white to off-white, circular/biconvex-shaped, non-film-coated scored tablets, coded ACF on one side and 004 on the other. They are supplied as follows: - NDC 0186-0004-31 unit of use bottles of 30. - No. 3780 — Tablets candesartan cilexetil, 8 mg, are light pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACG on one side and 008 on the other. They are supplied as follows: - NDC 0186-0008-31 unit of use bottles of 30. - No. 3781 — Tablets candesartan cilexetil, 16 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACH on one side and 016 on the other. They are supplied as follows: - NDC 0186-0016-31 unit of use bottles of 30 - NDC 0186-0016-54 unit of use bottles of 90 - NDC 0186-0016-28 unit dose packages of 100. - No. 3791 — Tablets candesartan cilexetil, 32 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACL on one side and 032 on the other. They are supplied as follows: - NDC 0186-0032-31 unit of use bottles of 30 - NDC 0186-0032-54 unit of use bottles of 90 - NDC 0186-0032-28 unit dose packages of 100. ## Storage - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) . - Keep container tightly closed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Tablets - Read the Patient information that comes with candesartan cilexetil before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about candesartan cilexetil, ask your doctor or pharmacist. - What is the most important information I should know about candesartan cilexetil? - Candesartan cilexetil can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking :- Candesartan cilexetil, tell your doctor right away. - What is candesartan cilexetil? - Candesartan cilexetil is a prescription medicine called an angiotensin receptor blocker (ARB). - Candesartan cilexetil is used to: - Treat high blood pressure in adults and children, 1 to 17 years of age - Treat certain types of heart failure in adults, to reduce death and hospitalization for heart damage and heart failure - Heart failure is a condition where the heart does not pump blood as well as it should. candesartan cilexetil must not be used in children less than 1 year of age for high blood pressure. - Who should not take candesartan cilexetil? - Do not take candesartan cilexetil if you: - are allergic to any of the ingredients in candesartan cilexetil. See the end of this leaflet for a complete list of ingredients in candesartan cilexetil. - are diabetic and taking aliskiren. - What should I tell my doctor before taking candesartan cilexetil? - Before you take candesartan cilexetil, tell your doctor if you: - have heart problems - have liver problems - have kidney problems - currently have vomiting or diarrhea - are scheduled for surgery or anesthesia. Low blood pressure can happen in people who take candesartan cilexetil and have major surgery and anesthesia. - have any other medical conditions - are pregnant or planning to become pregnant. See “What is the most important information I should know about candesartan cilexetil?” - are breast-feeding or plan to breast-feed. It is not known if candesartan cilexetil passes into your breast milk. You and your doctor should decide if you will take candesartan cilexetil or breast-feed. - You should not do both. - Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. candesartan cilexetil and other medicines may affect each other causing serious side effects. candesartan cilexetil may affect the way other medicines work, and other medicines may affect how candesartan cilexetil works. - Especially tell your doctor if you take: - lithium carbonate (Lithobid) or lithium citrate, medicines used in some types of depression - other medicines for high blood pressure, especially water pills (diuretics) - potassium supplements - salt substitutes - non-steroidal anti-inflammatory drugs (NSAIDs) - Know the medicines you take. Keep a list of your medications with you to show your doctor and pharmacist when a new medication is prescribed. Talk to your doctor or pharmacist before you start taking any new medicine. Your doctor or pharmacist will know what medicines are safe to take together. - How should I take candesartan cilexetil? - Take candesartan cilexetil exactly as prescribed by your doctor. - Do not change your dose or stop candesartan cilexetil without talking to your doctor, even if you are feeling well. - If your child cannot swallow tablets, or if tablets are not available in the prescribed strength, your pharmacist will prepare candesartan cilexetil as a liquid suspension for your child. If your child switches between taking the tablet and the suspension, your doctor will change the dose as needed. Shake the bottle of suspension well before each dose. - Candesartan cilexetil is taken by mouth with or without food. - If you miss a dose of candesartan cilexetil, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose on time. Do not take 2 doses at one time. If you are not sure about your dosing call your doctor or pharmacist. - If you take more candesartan cilexetil than prescribed, call your doctor, local poison control center, or go to the nearest emergency room. - What should I avoid while taking candesartan cilexetil? - Candesartan cilexetil can cause you to feel dizzy or tired. Do not drive, operate machinery, or do other dangerous activities until you know how candesartan cilexetil affects you. - What are the possible side effects of candesartan cilexetil? - Candesartan cilexetil may cause serious side effects, including: - Injury or death to your unborn baby. See “What is the most important information I should know about candesartan cilexetil? - Low blood pressure (hypotension). Low blood pressure is most likely to happen if you: - Take water pills (diuretics) - Are on a low salt diet - Get dialysis treatments - Are dehydrated (decreased body fluids) due to vomiting and diarrhea - Have heart problems - If you feel dizzy or faint lie down and call your doctor right away. - Low blood pressure can also happen if you have major surgery or anesthesia. You will be monitored for this and treated if needed. See “What should I tell my doctor before taking candesartan cilexetil?” - Worsening kidney problems. Kidney problems may get worse in people that already have kidney disease or heart problems. Your doctor may do blood tests to check for this. - Increased potassium in your blood. Your doctor may do a blood test to check your potassium levels as needed. - Symptoms of allergic reaction. Call your doctor right away if you have any of these symptoms of an allergic reaction: - Swelling of your face, lips, tongue or throat - Rash - Hives and itching - The most common side effects of candesartan cilexetil are: - Back pain - Dizziness - Cold or flu symptoms (upper respiratory tract infection) - Sore throat (pharyngitis) - Nasal congestion and stuffiness (rhinitis) - Tell your doctor or pharmacist about any side effect that bothers you or that does not go away. - These are not all the side effects of candesartan cilexetil. Ask your doctor or pharmacist for more information. - Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088. - How should I store candesartan cilexetil? - Do not keep medicine that is out of date or that you no longer need. - Store candesartan cilexetil Tablets at room temperature below 86°F (30°C). - Store candesartan cilexetil oral suspension at room temperature below 86°F (30°C). - Use the oral suspension within 30 days after first opening the bottle. Do not use after the expiration date stated on the bottle. - Do not freeze. - Keep the container of candesartan cilexetil closed tightly. - Keep candesartan cilexetil and all medicine out of the reach of children. - General information about candesartan cilexetil. - Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use v for a condition for which it was not prescribed. Do not give candesartan cilexetil to other people, even if they have the same problem you have. It may harm them. - This leaflet summarizes the most important information about candesartan cilexetil. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about candesartan cilexetil that is written for health professionals. This Patient Information has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol Alcohol-Candesartan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Atacand # Look-Alike Drug Names - Atacand - antacid # Drug Shortage Status # Price	Candesartan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, 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 Candesartan is an angiotensin II receptor blocker that is FDA approved for the {{{indicationType}}} of hypertension and heart failure. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, backache, dizziness, pharyngitis, rhinitis and upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Starting dosage: - 16 mg/day, as monotherapy, in non-volume depleted patients. - Use in hepatic impairment: - Initiate with 8 mg/day. If blood pressure is not controlled by candesartan cilexetil alone, a diuretic may be added. - Candesartan cilexetil may be administered with other antihypertensive agents. - Initial dosage: - 4 mg/day - Target dosage, achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient: - 32 mg/day ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of candesartan cilexetil in adult patients. ### Non–Guideline-Supported Use - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - 1 to < 17 Years of age Candesartan cilexetil may be administered once daily or divided into two equal doses. - In children 1 - 6 years of age: - Initial dosage: - 0.20 mg/kg/day PO - Further dosages: - 0.05 to 0.4 mg/kg per day PO - Children 6 - 17 years of age: - Less than 50 kg - Initial dosage: - 4 to 8 mg/day PO - Further dosages: - 2 to 16 mg per day PO - Greater than 50 kg - Initial dosage: - 8 to 16 mg/day PO - Further dosages: - 4 to 32 mg/day PO - For patients who can not swallow a pill, follow the instructions below for preparation of the suspension. The number of tablets and volume of vehicle specified below will yield 160 mL of a 1 mg/mL suspension: - Prepare the vehicle by adding equal volumes of 1Ora-Plus® (80 mL) and 1Ora-Sweet SF® (80 mL) or, alternatively, use, 1,2Ora-Blend SF® (160 mL). - Add a small amount of vehicle to the required number of ATACAND tablets (five 32 mg tablets) and grind into a smooth paste using a mortar and pestle. - Add the paste to a preparation vessel of suitable size. - Rinse the mortar and pestle clean using the vehicle and add this to the vessel. Repeat, if necessary. - Prepare the final volume by adding the remaining vehicle. - Mix thoroughly. - Dispense into suitably sized amber PET bottles. - Label with an expiry date of 100 days and include the following instructions: - Store at room temperature (below 30°C/86°F). Use within 30 days after first opening. Do not use after the expiry date stated on the bottle. - Do not freeze. - Shake well before each use. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of candesartan cilexetil in children. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non-Guideline-Supported Use of candesartan cilexetil in adult patients. # Contraindications - Hypersensitivity to candesartan. - Do not co-administer aliskiren with candesartan cilexetil in diabetic patients. # 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 - Death - When pregnancy is detected, discontinue candesartan cilexetil as soon as possible. - Oral doses ≥10 mg of candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. The 10-mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32 mg on a mg/m2 basis (comparison assumes human body weight of 50 kg). - Candesartan cilexetil given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m2 basis) caused maternal toxicity (decreased body weight and death) but, in surviving dams, had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development. - No maternal toxicity or adverse effects on fetal development were observed when oral doses up to 1000 mg of candesartan cilexetil/kg/day (approximately 138 times the MRHD on a mg/m2 basis) were administered to pregnant mice. - Children < 1 year of age must not receive candesartan cilexetil for hypertension. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys. - Candesartan cilexetil can cause symptomatic hypotension. - 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. - Patients with symptomatic hypotension may require temporarily reducing the dose of candesartan cilexetil, diuretic or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with candesartan cilexetil. - In the CHARM program (heart failure patients), hypotension was reported in 18.8% of patients on candesartan cilexetil versus 9.8% of patients on placebo. The incidence of hypotension leading to drug discontinuation in candesartan cilexetil-treated patients was 4.1% compared with 2.0% in placebo-treated patients. In the CHARM-Added program, where candesartan or placebo was given in addition to ACE inhibitors, hypotension was reported in 22.6% of patients treated with candesartan cilexetil versus 13.8% treated with placebo. - Monitoring of blood pressure is recommended during dose escalation and periodically thereafter. - Major Surgery/Anesthesia - Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists, including candesartan cilexetil, due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors. - Monitor renal function periodically in patients treated with candesartan cilexetil. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend, in part, on the activity of the renin-angiotensin system (e.g., patient with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia or acute renal failure when treated with candesartan cilexetil. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil. - In the CHARM program (heart failure patients), the incidence of abnormal renal function (e.g., creatinine increase) was 12.5% in patients treated with candesartan cilexetil versus 6.3% in patients treated with placebo. The incidence of abnormal renal function (e.g., creatinine increase) leading to drug discontinuation in candesartan cilexetil-treated patients was 6.3% compared with 2.9% in placebo-treated patients. In the CHARM-Added program, where candesartan or placebo was given in addition to ACE inhibitors, the incidence of abnormal renal function (e.g., creatinine increase) was 15% in patients treated with candesartan cilexetil versus 9% in patients treated with placebo. - Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. - Monitor serum potassium periodically. - In the CHARM program (heart failure patients), the incidence of hyperkalemia was 6.3% in patients treated with candesartan cilexetil versus 2.1% in patients treated with placebo. The incidence of hyperkalemia leading to drug discontinuation in candesartan cilexetil-treated patients was 2.4% compared with 0.6% in placebo-treated patients. In the CHARM-Added program where candesartan or placebo was given in addition to ACE inhibitors, the incidence of hyperkalemia was 9.5% in patients treated with candesartan cilexetil versus 3.5% in patients treated with placebo. # Adverse Reactions ## Clinical Trials Experience - Adult Hypertension: - 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. - Candesartan cilexetil has been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied for at least 6 months and about 200 for at least 1 year. In general, treatment with candesartan cilexetil was well tolerated. The overall incidence of adverse events reported with candesartan cilexetil was similar to placebo. - The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (ie, 108 of 3260) of patients treated with candesartan cilexetil as monotherapy and 3.5% (ie, 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (ie, 57 of 2350) of patients treated with candesartan cilexetil and 3.4% (ie, 35 of 1027) of patients treated with placebo. - Pediatric hypertension - Among children in clinical studies, 1 in 93 children age 1 to < 6 and 3 in 240 age 6 to < 17 experienced worsening renal disease. The association between candesartan and exacerbation of the underlying condition could not be excluded. - Heart failure - The adverse event profile of candesartan cilexetil in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing candesartan cilexetil in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued candesartan cilexetil for adverse events vs. 16.1% of placebo patients. - Headache - Dizziness - Heart Failure - Upper respiratory tract infection - Pharyngitis - Rhinitis - Back pain ## Postmarketing Experience - The following adverse reactions were identified during post-approval use of candesartan cilexetil. 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. - Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. The following have been very rarely reported in post-marketing experience: - Abnormal hepatic function - Hepatitis - Neutropenia - Leukopenia - Agranulocytosis - Angioedema - Hyperkalemia - Hyponatremia - Cough - Pruritus - Rash - Urticaria # Drug Interactions - Lithium - NSAIDS - Dual inhibition of the renin-angiotensin system - Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, and with some angiotensin II receptor antagonists. - An increase in serum lithium concentration has been reported during concomitant administration of lithium with candesartan cilexetil. - Monitor serum lithium levels. - Including Selective Cyclooxygenase-2 Inhibitors (COX-2 inhibitors). - In elderly patients, 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 candesartan, may result in deterioration of renal function, including possible acute renal failure. - These effects are usually reversible. - Monitor renal function periodically in patients receiving candesartan and NSAID therapy. - The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors. - 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 candesartan cilexetil and other agents that affect the RAS. - Do not co-administer aliskiren with candesartan celexetil in patients with diabetes. - Avoid use of aliskiren with candesartan celexetil 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 - Death - When pregnancy is detected, discontinue candesartan celexetil as soon as possible. - These adverse outcomes are usually associated with use of similar drugs in the second and third trimester of pregnancy. - Most epidemiological 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 candesartan celexetil, 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 candesartan celexetil for hypotension, oliguria, and hyperkalemia. Pregnancy Category (AUS): D There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of candesartan celexetil in women who are pregnant. ### Labor and Delivery The effect of candesartan celexetil on labor and delivery in humans is unknown. ### Nursing Mothers - It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be present in rat milk. - Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue candesartan celexetil, taking into account the importance of the drug to the mother. ### Pediatric Use - Neonates with a history of in utero exposure to candesartan celexetil: - 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 candesartan celexetil were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies. The pharmacokinetics of candesartan celexetil have been evaluated in pediatric patients 1 to < 17 years of age. - Children < 1 year of age must not receive candesartan celexetil for hypertension. ### Geriatic Use There is no FDA guidance on the use of Candesartan in geriatric settings. ### Gender There is no FDA guidance on the use of Candesartan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Candesartan with respect to specific racial populations. ### Renal Impairment - In hypertensive patients with renal insufficiency, serum concentrations of candesartan are elevated. - After repeated dosing, the AUC and Cmax were noted to be approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m2) compared to patients with normal kidney function. - The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. - Candesartan cannot be removed by hemodialysis. - No initial dosage adjustment is necessary in patients with renal insufficiency. - In heart failure patients with renal impairment, AUC0-72h was noted to be 36% and 65% higher in mild and moderate renal impairment, respectively. Cmax was 15% and 55% higher in mild and moderate renal impairment, respectively. ### Hepatic Impairment - The pharmacokinetics of candesartan were compared in patients with mild and moderate hepatic impairment to matched healthy volunteers following a single oral dose of 16 mg candesartan cilexetil. - The increase in AUC for candesartan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in Cmax for candesartan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. - The pharmacokinetics after candesartan cilexetil administration have not been investigated in patients with severe hepatic impairment. No initial dosage adjustment is necessary in patients with mild hepatic impairment. In hypertensive patients with moderate hepatic impairment, consideration should be given to initiation of candesartan at a lower dose ### Females of Reproductive Potential and Males - There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg). - Candesartan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. - Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. - Candesartan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results. Candesartan cilexetil was not evaluated in the CHL chromosomal aberration or CHO gene mutation assay. - Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of up to 300 mg/kg/day (83 times the maximum daily human dose of 32 mg on a body surface area basis). ### Immunocompromised Patients There is no FDA guidance one the use of Candesartan in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - 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 - Death - When pregnancy is detected, discontinue candesartan cilexetil as soon as possible. - Children < 1 year of age must not receive candesartan cilexetil for hypertension. - Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys. - Candesartan cilexetil can cause symptomatic hypotension. - 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. - Patients with symptomatic hypotension may require temporarily reducing the dose of candesartan cilexetil, diuretic or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with candesartan cilexetil. - Monitoring of blood pressure is recommended during dose escalation and periodically thereafter. - Monitor renal function periodically in patients treated with candesartan cilexetil. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend, in part, on the activity of the renin-angiotensin system (e.g., patient with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia or acute renal failure when treated with candesartan cilexetil. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil. - Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. - Monitor serum potassium periodically. # IV Compatibility There is limited information regarding the compatibility of candesartan cilexetil and IV administrations. # Overdosage - No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. - The most likely manifestation of overdosage with candesartan cilexetil would be: - Hypotension - Dizziness - Tachycardia - Bradycardia, could occur from parasympathetic (vagal) stimulation. - If symptomatic hypotension should occur, supportive treatment should be instituted. - Candesartan cannot be removed by hemodialysis. - Treatment: To obtain up-to-date information about the treatment of overdose, consult your 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 overdoses, drug-drug interactions, and altered pharmacokinetics in your patient. # Pharmacology ## Mechanism of Action - Angiotensin II is 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, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. - Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis. - There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. * Candesartan has much greater affinity (>10,000-fold) for the AT1 receptor than for the AT2 receptor. - Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. - ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. - Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. - Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure. ## Structure - Candesartan cilexetil, a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract. - Candesartan is a selective AT1 subtype angiotensin II receptor antagonist. - Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester). Its empirical formula is C33H34N6O6, and its structural formula is: - Candesartan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral. ## Pharmacodynamics - Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. - After 1 week of once daily dosing with 8 mg of candesartan cilexetil, the pressor effect was inhibited by approximately 90% at peak with approximately 50% inhibition persisting for 24 hours. - Plasma concentrations of angiotensin I and angiotensin II, and plasma renin activity (PRA), increased in a dose-dependent manner after single and repeated administration of candesartan cilexetil to healthy subjects, hypertensive, and heart failure patients. - ACE activity was not altered in healthy subjects after repeated candesartan cilexetil administration. The once-daily administration of up to 16 mg of candesartan cilexetil to healthy subjects did not influence plasma aldosterone concentrations, but a decrease in the plasma concentration of aldosterone was observed when 32 mg of candesartan cilexetil was administered to hypertensive patients. In spite of the effect of candesartan cilexetil on aldosterone secretion, very little effect on serum potassium was observed. - Hypertension - Adults - In multiple-dose studies with hypertensive patients, there were no clinically significant changes in metabolic function, including serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a 12-week study of 161 patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension, there was no change in the level of HbA1c. - In heart failure patients, candesartan ≥ 8 mg resulted in decreases in systemic vascular resistance and pulmonary capillary wedge pressure. ## Pharmacokinetics - Distribution - The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that candesartan crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus. - Metabolism and Excretion - Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of 14C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of 14C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of candesartan. - Adults - Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT1 subtype angiotensin II receptor antagonist. Candesartan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. The elimination half-life of candesartan is approximately 9 hours. After single and repeated administration, the pharmacokinetics of candesartan are linear for oral doses up to 32 mg of candesartan cilexetil. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing. Following administration of candesartan cilexetil, the absolute bioavailability of candesartan was estimated to be 15%. After tablet ingestion, the peak serum concentration (Cmax) is reached after 3 to 4 hours. Food with a high fat content does not affect the bioavailability of candesartan after candesartan cilexetil administration. - Pediatrics - In children 1 to 17 years of age, plasma levels are greater than 10–fold higher at peak (approximately 4 hours) than 24 hours after a single dose. - Children 1 to < 6 years of age, given 0.2 mg/kg had exposure similar to adults given 8 mg. - Children > 6 years of age had exposure similar to adults given the same dose. - The pharmacokinetics (Cmax and AUC) were not modified by age, sex or body weight. - Candesartan cilexetil pharmacokinetics have not been investigated in pediatric patients less than 1 year of age. - From the dose-ranging studies of candesartan cilexetil, there was a dose related increase in plasma candesartan concentrations. - The renin-angiotensin system (RAS) plays a critical role in kidney development. RAS blockade has been shown to lead to abnormal kidney development in very young mice. Children < 1 year of age must not receive ATACAND. Administering drugs that act directly on the renin-angiotensin system (RAS) can alter normal renal development. - 'Geriatric and Sex - The pharmacokinetics of candesartan have been studied in the elderly (≥ 65 years) and in both sexes. The plasma concentration of candesartan was higher in the elderly (Cmax was approximately 50% higher, and AUC was approximately 80% higher) compared to younger subjects administered the same dose. The pharmacokinetics of candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration. No initial dosage adjustment is necessary. There is no difference in the pharmacokinetics of candesartan between male and female subjects. - Renal Insufficiency - In hypertensive patients with renal insufficiency, serum concentrations of candesartan were elevated. After repeated dosing, the AUC and Cmax were approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m2) compared to patients with normal kidney function. The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. Candesartan cannot be removed by hemodialysis. No initial dosage adjustment is necessary in patients with renal insufficiency [see DOSAGE AND ADMINISTRATION (2.1)]. - In heart failure patients with renal impairment, AUC0-72h was 36% and 65% higher in mild and moderate renal impairment, respectively. Cmax was 15% and 55% higher in mild and moderate renal impairment, respectively. - Pediatrics: Candesartran cilexetil pharmacokinetics have not been determined in children with renal insufficiency. - Hepatic Insufficiency - The pharmacokinetics of candesartan were compared in patients with mild and moderate hepatic impairment to matched healthy volunteers following a single oral dose of 16 mg candesartan cilexetil. The increase in AUC for candesartan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in Cmax for candesartan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. The pharmacokinetics after candesartan cilexetil administration have not been investigated in patients with severe hepatic impairment. No initial dosage adjustment is necessary in patients with mild hepatic impairment. In hypertensive patients with moderate hepatic impairment, consideration should be given to initiation of candesartran cilexetil at a lower dose. - Heart Failure - The pharmacokinetics of candesartan were linear in patients with heart failure (NYHA class II and III) after candesartan cilexetil doses of 4, 8, and 16 mg. After repeated dosing, the AUC was approximately doubled in these patients compared with healthy, younger patients. The pharmacokinetics in heart failure patients is similar to that in healthy elderly volunteers. ## Nonclinical Toxicology - There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg). - Candesartan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. - Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. - Candesartan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results. Candesartan cilexetil was not evaluated in the CHL chromosomal aberration or CHO gene mutation assay. - Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of up to 300 mg/kg/day (83 times the maximum daily human dose of 32 mg on a body surface area basis). # Clinical Studies - Adult - The antihypertensive effects of candesartran cilexetil were examined in 14 placebo-controlled trials of 4- to 12-weeks duration, primarily at daily doses of 2 to 32 mg per day in patients with baseline diastolic blood pressures of 95 to 114 mm Hg. Most of the trials were of candesartan cilexetil as a single agent, but it was also studied as add-on to hydrochlorothiazide and amlodipine. These studies included a total of 2350 patients randomized to one of several doses of candesartan cilexetil and 1027 to placebo. Except for a study in diabetics, all studies showed significant effects, generally dose related, of 2 to 32 mg on trough (24 hour) systolic and diastolic pressures compared to placebo, with doses of 8 to 32 mg giving effects of about 8-12/4-8 mm Hg. There were no exaggerated first-dose effects in these patients. Most of the antihypertensive effect was seen within 2 weeks of initial dosing and the full effect in 4 weeks. With once-daily dosing, blood pressure effect was maintained over 24 hours, with trough to peak ratios of blood pressure effect generally over 80%. Candesartan cilexetil had an additional blood pressure lowering effect when added to hydrochlorothiazide. - The antihypertensive effects of candesartan cilexetil and losartan potassium at their highest recommended doses administered once-daily were compared in two randomized, double-blind trials. In a total of 1268 patients with mild to moderate hypertension who were not receiving other antihypertensive therapy, candesartan cilexetil 32 mg lowered systolic and diastolic blood pressure by 2 to 3 mm Hg on average more than losartan potassium 100 mg, when measured at the time of either peak or trough effect. The antihypertensive effects of twice daily dosing of either candesartan cilexetil or losartan potassium were not studied. - The antihypertensive effect was similar in men and women and in patients older and younger than 65. Candesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population). This has been generally true for angiotensin II antagonists and ACE inhibitors. In long-term studies of up to 1 year, the antihypertensive effectiveness of candesartan cilexetil was maintained, and there was no rebound after abrupt withdrawal. - There were no changes in the heart rate of patients treated with candesartan cilexetil in controlled trials. - Pediatric - The antihypertensive effects of candesartran cilexetil were evaluated in hypertensive children 1 to < 6 years old and 6 to < 17 years of age in two randomized, double-blind multicenter, 4-week dose ranging studies. There were 93 patients 1 to < 6 years of age, 74% of whom had renal disease, that were randomized to receive an oral dose of candesartan cilexetil suspension 0.05, 0.20 or 0.40 mg/kg once daily. The primary method of analysis was slope of the change in systolic blood pressure (SBP) as a function of dose. Since there was no placebo group, the change from baseline likely overestimates the true magnitude of blood pressure effect. Nevertheless, SBP and diastolic blood pressure (DBP) decreased 6.0/5.2 to 12.0/11.1 mmHg from baseline across the three doses of candesartan. - In children 6 to < 17 years, 240 patients were randomized to receive either placebo or low, medium, or high doses of candesartran cilexetil in a ratio of 1: 2: 2: 2. For children who weighed < 50 kg the doses of candesartran cilexetil were 2, 8, or 16 mg once daily. For those > 50 kg the candesartran cilexetil doses were 4, 16 or 32 mg once daily. Those enrolled were 47% Black and 29% were female; mean age +/- SD was 12.9 +/- 2.6 years. - The placebo subtracted effect at trough for sitting systolic blood pressure/sitting diastolic blood pressure for the different doses were from 4.9/3.0 to 7.5/6.2 mmHg. In children 6 to < 17 years there was a trend for a lesser blood pressure effect for Blacks compared to other patients. There were too few individuals in the age group of 1 - 6 years old to determine whether Blacks respond differently than other patients to candesartran cilexetil. - Candesartan was studied in two heart failure outcome studies: 1. The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity trial in patients intolerant of ACE inhibitors (CHARM–Alternative), 2. CHARM–Added in patients already receiving ACE inhibitors. Both studies were international double-blind, placebo-controlled trials in patients with NYHA class II - IV heart failure and LVEF ≤40%. In both trials, patients were randomized to placebo or candesartran cilexetil (initially 4-8 mg once daily, titrated as tolerated to 32 mg once daily) and followed for up to 4 years. Patients with serum creatinine > 3 mg/dL, serum potassium > 5.5 mEq/L, symptomatic hypotension or known bilateral renal artery stenosis were excluded. The primary end point in both trials was time to either cardiovascular death or hospitalization for heart failure. - CHARM–Alternative included 2028 subjects not receiving an ACE inhibitor due to intolerance. The mean age was 67 years and 32% were female, 48% were NYHA II, 49% were NYHA III, 4% were NYHA IV, and the mean ejection fraction was 30%. Sixty-two percent had a history of myocardial infarction, 50% had a history of hypertension, and 27% had diabetes. Concomitant drugs at baseline were diuretics (85%), digoxin (46%), beta-blockers (55%), and spironolactone (24%). The mean daily dose of candesartran cilexetil was approximately 23 mg and 59% of subjects on treatment received 32 mg once daily. - After a median follow-up of 34 months, there was a 23% reduction in the risk of cardiovascular death or heart failure hospitalization on candesartran cilexetil (p<0.001), with both components contributing to the overall effect (Table 1). - In CHARM–Added, 2548 subjects receiving an ACE inhibitor were randomized to candesartran cilexetil or placebo. The specific ACE inhibitor and dose were at the discretion of the investigators, who were encouraged to titrate patients to doses known to be effective in clinical outcome trials, subject to patient tolerability. Forced titration to maximum tolerated doses of ACE inhibitor was not required. - The mean age was 64 years and 21% were female, 24% were NYHA II, 73% were NYHA III, 3% were NYHA IV, and the mean ejection fraction was 28%. Fifty-six percent had a history of myocardial infarction, 48% had a history of hypertension, and 30% had diabetes. Concomitant drugs at baseline in addition to ACE inhibitors were diuretics (90%), digoxin (58%), beta-blockers (55%), and spironolactone (17%). The mean daily dose of candesartran cilexetil was approximately 24 mg and 61% of subjects on treatment received 32 mg once daily. After a median follow-up of 41 months, there was a 15% reduction in the risk of cardiovascular death or heart failure hospitalization on candesartran cilexetil (p=0.011), with both components contributing to the overall effect (Table 2). There was no evident relationship between dose of ACE inhibitor and the benefit of candesartran cilexetil. - In these two studies, the benefit of candesartran cilexetil in reducing the risk of CV death or heart failure hospitalization (18% p<0.001) was evident in major subgroups (see Figure), and in patients on other combinations of cardiovascular and heart failure treatments, including ACE inhibitors and beta-blockers. CV Death or Heart Failure Hospitalization in Subgroups – LV Systolic Dysfunction Trials # How Supplied - No. 3782 — Tablets candesartan cilexetil, 4 mg, are white to off-white, circular/biconvex-shaped, non-film-coated scored tablets, coded ACF on one side and 004 on the other. They are supplied as follows: - NDC 0186-0004-31 unit of use bottles of 30. - No. 3780 — Tablets candesartan cilexetil, 8 mg, are light pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACG on one side and 008 on the other. They are supplied as follows: - NDC 0186-0008-31 unit of use bottles of 30. - No. 3781 — Tablets candesartan cilexetil, 16 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACH on one side and 016 on the other. They are supplied as follows: - NDC 0186-0016-31 unit of use bottles of 30 - NDC 0186-0016-54 unit of use bottles of 90 - NDC 0186-0016-28 unit dose packages of 100. - No. 3791 — Tablets candesartan cilexetil, 32 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACL on one side and 032 on the other. They are supplied as follows: - NDC 0186-0032-31 unit of use bottles of 30 - NDC 0186-0032-54 unit of use bottles of 90 - NDC 0186-0032-28 unit dose packages of 100. ## Storage - Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. - Keep container tightly closed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Tablets - Read the Patient information that comes with candesartan cilexetil before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about candesartan cilexetil, ask your doctor or pharmacist. - What is the most important information I should know about candesartan cilexetil? - Candesartan cilexetil can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking :* Candesartan cilexetil, tell your doctor right away. - What is candesartan cilexetil? - Candesartan cilexetil is a prescription medicine called an angiotensin receptor blocker (ARB). - Candesartan cilexetil is used to: - Treat high blood pressure in adults and children, 1 to 17 years of age - Treat certain types of heart failure in adults, to reduce death and hospitalization for heart damage and heart failure - Heart failure is a condition where the heart does not pump blood as well as it should. candesartan cilexetil must not be used in children less than 1 year of age for high blood pressure. - Who should not take candesartan cilexetil? - Do not take candesartan cilexetil if you: - are allergic to any of the ingredients in candesartan cilexetil. See the end of this leaflet for a complete list of ingredients in candesartan cilexetil. - are diabetic and taking aliskiren. - What should I tell my doctor before taking candesartan cilexetil? - Before you take candesartan cilexetil, tell your doctor if you: - have heart problems - have liver problems - have kidney problems - currently have vomiting or diarrhea - are scheduled for surgery or anesthesia. Low blood pressure can happen in people who take candesartan cilexetil and have major surgery and anesthesia. - have any other medical conditions - are pregnant or planning to become pregnant. See “What is the most important information I should know about candesartan cilexetil?” - are breast-feeding or plan to breast-feed. It is not known if candesartan cilexetil passes into your breast milk. You and your doctor should decide if you will take candesartan cilexetil or breast-feed. - You should not do both. - Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. candesartan cilexetil and other medicines may affect each other causing serious side effects. candesartan cilexetil may affect the way other medicines work, and other medicines may affect how candesartan cilexetil works. - Especially tell your doctor if you take: - lithium carbonate (Lithobid) or lithium citrate, medicines used in some types of depression - other medicines for high blood pressure, especially water pills (diuretics) - potassium supplements - salt substitutes - non-steroidal anti-inflammatory drugs (NSAIDs) - Know the medicines you take. Keep a list of your medications with you to show your doctor and pharmacist when a new medication is prescribed. Talk to your doctor or pharmacist before you start taking any new medicine. Your doctor or pharmacist will know what medicines are safe to take together. - How should I take candesartan cilexetil? - Take candesartan cilexetil exactly as prescribed by your doctor. - Do not change your dose or stop candesartan cilexetil without talking to your doctor, even if you are feeling well. - If your child cannot swallow tablets, or if tablets are not available in the prescribed strength, your pharmacist will prepare candesartan cilexetil as a liquid suspension for your child. If your child switches between taking the tablet and the suspension, your doctor will change the dose as needed. Shake the bottle of suspension well before each dose. - Candesartan cilexetil is taken by mouth with or without food. - If you miss a dose of candesartan cilexetil, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose on time. Do not take 2 doses at one time. If you are not sure about your dosing call your doctor or pharmacist. - If you take more candesartan cilexetil than prescribed, call your doctor, local poison control center, or go to the nearest emergency room. - What should I avoid while taking candesartan cilexetil? - Candesartan cilexetil can cause you to feel dizzy or tired. Do not drive, operate machinery, or do other dangerous activities until you know how candesartan cilexetil affects you. - What are the possible side effects of candesartan cilexetil? - Candesartan cilexetil may cause serious side effects, including: - Injury or death to your unborn baby. See “What is the most important information I should know about candesartan cilexetil? - Low blood pressure (hypotension). Low blood pressure is most likely to happen if you: - Take water pills (diuretics) - Are on a low salt diet - Get dialysis treatments - Are dehydrated (decreased body fluids) due to vomiting and diarrhea - Have heart problems - If you feel dizzy or faint lie down and call your doctor right away. - Low blood pressure can also happen if you have major surgery or anesthesia. You will be monitored for this and treated if needed. See “What should I tell my doctor before taking candesartan cilexetil?” - Worsening kidney problems. Kidney problems may get worse in people that already have kidney disease or heart problems. Your doctor may do blood tests to check for this. - Increased potassium in your blood. Your doctor may do a blood test to check your potassium levels as needed. - Symptoms of allergic reaction. Call your doctor right away if you have any of these symptoms of an allergic reaction: - Swelling of your face, lips, tongue or throat - Rash - Hives and itching - The most common side effects of candesartan cilexetil are: - Back pain - Dizziness - Cold or flu symptoms (upper respiratory tract infection) - Sore throat (pharyngitis) - Nasal congestion and stuffiness (rhinitis) - Tell your doctor or pharmacist about any side effect that bothers you or that does not go away. - These are not all the side effects of candesartan cilexetil. Ask your doctor or pharmacist for more information. - Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088. - How should I store candesartan cilexetil? - Do not keep medicine that is out of date or that you no longer need. - Store candesartan cilexetil Tablets at room temperature below 86°F (30°C). - Store candesartan cilexetil oral suspension at room temperature below 86°F (30°C). - Use the oral suspension within 30 days after first opening the bottle. Do not use after the expiration date stated on the bottle. - Do not freeze. - Keep the container of candesartan cilexetil closed tightly. - Keep candesartan cilexetil and all medicine out of the reach of children. - General information about candesartan cilexetil. - Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use v for a condition for which it was not prescribed. Do not give candesartan cilexetil to other people, even if they have the same problem you have. It may harm them. - This leaflet summarizes the most important information about candesartan cilexetil. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about candesartan cilexetil that is written for health professionals. This Patient Information has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol Alcohol-Candesartan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Atacand # Look-Alike Drug Names - Atacand - antacid[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Candesartan
6fbd5b00c27f27c3901f03980e7acc41f3298423	wikidoc	CankerMelts	CankerMelts CankerMelts is a non-prescription medication for canker sores sold by Orahealth Corporation, a privately held company based in Bellevue, WA. The active ingredient is licorice extract, with collagen added which may help soothe pain and accelerate healing. CankerMelts is an all-natural self-adhering patch that sticks directly on the sore, delivering time-released medication over 2-6 hours. # History Invented by patent attorney Jeff Haley, CankerMelts was first sold online at Amazon.com in 2004. In 2006, clinical tests at the University of Washington found that CankerMelts relieves pain and reduces the healing time of canker sores from 1-2 weeks to 1-5 days. Active ingredient Glycyrrhiza extract (licorice) has been used for over 4000 years as an herbal remedy, including use in Traditional Chinese Medicine as a treatment for all varieties of ulcers. CankerMelts combines this natural remedy with a new oral patch technology that allows a fully-dissolving troche to adhere directly to the afflicted region.	CankerMelts CankerMelts is a non-prescription medication for canker sores sold by Orahealth Corporation, a privately held company based in Bellevue, WA. The active ingredient is licorice extract, with collagen added which may help soothe pain and accelerate healing. CankerMelts is an all-natural self-adhering patch that sticks directly on the sore, delivering time-released medication over 2-6 hours. # History Invented by patent attorney Jeff Haley, CankerMelts was first sold online at Amazon.com in 2004. In 2006, clinical tests at the University of Washington found that CankerMelts relieves pain and reduces the healing time of canker sores from 1-2 weeks to 1-5 days. Active ingredient Glycyrrhiza extract (licorice) has been used for over 4000 years as an herbal remedy, including use in Traditional Chinese Medicine as a treatment for all varieties of ulcers. CankerMelts combines this natural remedy with a new oral patch technology that allows a fully-dissolving troche to adhere directly to the afflicted region. # External links Orahealth Corporation, producer of CankerMelts	https://www.wikidoc.org/index.php/CankerMelts
60ce5767b0a7250f364f4df6dbd57ba42c52f854	wikidoc	Cannabidiol	Cannabidiol # Overview Cannabidiol, also known as CBD, is an antipsychotic cannabinoid found in the hemp plant Cannabis sativa. It is a major constituent of the plant, representing up to 40% in its extracts. CBD alone is not intoxicating, but it appears to affect the euphoric effect of THC (which is an isomer of cannabidiol) and add a sedative quality. Some research, however, indicates that CBD can increase alertness. It may decrease the rate of THC clearance from the body, perhaps by interfering with the metabolism of THC in the liver. CBD does not appear to affect either the CB1 or CB2 receptors. Medically, it appears to relieve convulsion, inflammation, anxiety, and nausea, as well as inhibit cancer cell growth. Recent studies have shown cannabidiol to be as effective as atypical antipsychotics in treating schizophrenia. # Medicinal use In April 2005, Canadian authorities approved the marketing of Sativex, a mouth spray for multiple sclerosis to alleviate pain. Sativex contains tetrahydrocannabinol together with cannabidiol. It is marketed in Canada by GW Pharmaceuticals. Cannabidiol has also been shown to inhibit cancer cell growth, with low potency in non-cancer cells. Although the inhibitory mechanism is not yet fully understood, Ligresti et al suggest that "cannabidiol exerts its effects on these cells through a combination of mechanisms that include either direct or indirect activation of CB2 and TRPV1 receptors, and induction of oxidative stress, all contributing to induce apoptosis."	Cannabidiol # Overview Cannabidiol, also known as CBD, is an antipsychotic cannabinoid found in the hemp plant Cannabis sativa. It is a major constituent of the plant, representing up to 40% in its extracts.[1] CBD alone is not intoxicating, but it appears to affect the euphoric effect of THC (which is an isomer of cannabidiol) and add a sedative quality[citation needed]. Some research, however, indicates that CBD can increase alertness.[2] It may decrease the rate of THC clearance from the body, perhaps by interfering with the metabolism of THC in the liver. CBD does not appear to affect either the CB1 or CB2 receptors.[3] Medically, it appears to relieve convulsion, inflammation, anxiety, and nausea, as well as inhibit cancer cell growth[citation needed]. Recent studies have shown cannabidiol to be as effective as atypical antipsychotics in treating schizophrenia.[4] # Medicinal use In April 2005, Canadian authorities approved the marketing of Sativex, a mouth spray for multiple sclerosis to alleviate pain. Sativex contains tetrahydrocannabinol together with cannabidiol. It is marketed in Canada by GW Pharmaceuticals. Cannabidiol has also been shown to inhibit cancer cell growth, with low potency in non-cancer cells. Although the inhibitory mechanism is not yet fully understood, Ligresti et al suggest that "cannabidiol exerts its effects on these cells through a combination of mechanisms that include either direct or indirect activation of CB2 and TRPV1 receptors, and induction of oxidative stress, all contributing to induce apoptosis."[5]	https://www.wikidoc.org/index.php/Cannabidiol
a7cab6567d5c6bb754058d905f2062e6ddd2d7c0	wikidoc	Capacitance	Capacitance Capacitance is a measure of the amount of electric charge stored (or separated) for a given electric potential. The most common form of charge storage device is a two-plate capacitor. If the charges on the plates are +Q and −Q, and V gives the voltage difference between the plates, then the capacitance is given by The SI unit of capacitance is the farad; 1 farad = 1 coulomb per volt. # Energy The energy (measured in joules) stored in a capacitor is equal to the work done to charge it. Consider a capacitance C, holding a charge +q on one plate and -q on the other. Moving a small element of charge \mathrm{d}q from one plate to the other against the potential difference V = q/C requires the work \mathrm{d}W: where We can find the energy stored in a capacitance by integrating this equation. Starting with an uncharged capacitance (q=0) and moving charge from one plate to the other until the plates have charge +Q and -Q requires the work W: Combining this with the above equation for the capacitance of a flat-plate capacitor, we get: where # Capacitance and 'displacement current' The physicist James Clerk Maxwell invented the concept of displacement current, \frac{\partial \vec{D}}{\partial t}, to make Ampère's law consistent with conservation of charge in cases where charge is accumulating, for example in a capacitor. He interpreted this as a real motion of charges, even in vacuum, where he supposed that it corresponded to motion of dipole charges in the ether. Although this interpretation has been abandoned, Maxwell's correction to Ampère's law remains valid (a changing electric field produces a magnetic field). Maxwell's equation combining Ampère's law with the displacement current concept is given as \vec{\nabla} \times \vec{H} = \vec{J} + \frac{\partial \vec{D}}{\partial t}. (Integrating both sides, the integral of \vec{\nabla}\times \vec{H} can be replaced — courtesy of Stokes's theorem — with the integral of \vec{H} \cdot \mathrm{d} \vec{l} over a closed contour, thus demonstrating the interconnection with Ampère's formulation.) # Coefficients of Potential The discussion above is limited to the case of two conducting plates, although of arbitrary size and shape. The definition C=Q/V still holds if only one plate is given a charge, provided that we recognize that the field lines produced by that charge terminate as if the plate were at the center of an oppositely charged sphere at infinity. C=Q/V does not apply when there are more than two charged plates, or when the net charge on the two plates is non-zero. To handle this case, Maxwell introduced his "coefficients of potential". If three plates are given charges Q_1, Q_2, Q_3, then the voltage of plate 1 is given by and similarly for the other voltages. Maxwell showed that the coefficients of potential are symmetric, so that p_{12}=p_{21}, etc. # Capacitance/inductance duality In mathematical terms, the ideal capacitance can be considered as an inverse of the ideal inductance, because the voltage-current equations of the two phenomena can be transformed into one another by exchanging the voltage and current terms. # Self-capacitance In electrical circuits, the term capacitance is usually a shorthand for the mutual capacitance between two adjacent conductors, such as the two plates of a capacitor. There also exists a property called self-capacitance, which is the amount of electrical charge that must be added to an isolated conductor to raise its electrical potential by one volt. The reference point for this potential is a theoretical hollow conducting sphere, of infinite radius, centred on the conductor. Using this method, the self-capacitance of a conducting sphere of radius R is given by: Typical values of self-capacitance are: - for the top "plate" of a van de Graaf generator, typically a sphere 20 cm in radius: 20 pF - the planet Earth: about 710 µF # Elastance The inverse of capacitance is called elastance, and its unit is the reciprocal farad, also informally called the daraf. # Stray capacitance Any two adjacent conductors can be considered as a capacitor, although the capacitance will be small unless the conductors are close together or long. This (unwanted) effect is termed "stray capacitance". Stray capacitance can allow signals to leak between otherwise isolated circuits (an effect called crosstalk), and it can be a limiting factor for proper functioning of circuits at high frequency. Stray capacitance is often encountered in amplifier circuits in the form of "feedthrough" capacitance that interconnects the input and output nodes (both defined relative to a common ground). It is often convenient for analytical purposes to replace this capacitance with a combination of one input-to-ground capacitance and one output-to-ground capacitance. (The original configuration — including the input-to-output capacitance — is often referred to as a pi-configuration.) Miller's theorem can be used to effect this replacement. Miller's theorem states that, if the gain ratio of two nodes is 1:K, then an impedance of Z connecting the two nodes can be replaced with a Z/(1-k) impedance between the first node and ground and a KZ/(K-1) impedance between the second node and ground. (Since impedance varies inversely with capacitance, the internode capacitance, C, will be seen to have been replaced by a capacitance of KC from input to ground and a capacitance of (K-1)C/K from output to ground.) When the input-to-output gain is very large, the equivalent input-to-ground impedance is very small while the output-to-ground impedance is essentially equal to the original (input-to-output) impedance. # Capacitors The capacitance of the majority of capacitors used in electronic circuits is several orders of magnitude smaller than the farad. The most common subunits of capacitance in use today are the millifarad (mF), microfarad (µF), the nanofarad (nF) and the picofarad (pF) The capacitance can be calculated if the geometry of the conductors and the dielectric properties of the insulator between the conductors are known. For example, the capacitance of a parallel-plate capacitor constructed of two parallel plates of area A separated by a distance d is approximately equal to the following: where The equation is a good approximation if d is small compared to the other dimensions of the plates. In CGS units the equation has the form: where C in this case has the units of length. The dielectric constant for a number of very useful dielectrics changes as a function of the applied electrical field, e.g. ferroelectric materials, so the capacitance for these devices is no longer purely a function of device geometry. If a capacitor is driven with a sinusoidal voltage, the dielectric constant, or more accurately referred to as the relative static permittivity, is a function of frequency. A changing dielectric constant with frequency is referred to as a dielectric dispersion, and is governed by dielectric relaxation processes, such as Debye relaxation. # Footnotes	Capacitance Template:Electromagnetism3 Capacitance is a measure of the amount of electric charge stored (or separated) for a given electric potential. The most common form of charge storage device is a two-plate capacitor. If the charges on the plates are +Q and −Q, and V gives the voltage difference between the plates, then the capacitance is given by The SI unit of capacitance is the farad; 1 farad = 1 coulomb per volt. # Energy The energy (measured in joules) stored in a capacitor is equal to the work done to charge it. Consider a capacitance C, holding a charge +q on one plate and -q on the other. Moving a small element of charge <math>\mathrm{d}q</math> from one plate to the other against the potential difference V = q/C requires the work <math>\mathrm{d}W</math>: where We can find the energy stored in a capacitance by integrating this equation. Starting with an uncharged capacitance (q=0) and moving charge from one plate to the other until the plates have charge +Q and -Q requires the work W: Combining this with the above equation for the capacitance of a flat-plate capacitor, we get: where # Capacitance and 'displacement current' The physicist James Clerk Maxwell invented the concept of displacement current, <math>\frac{\partial \vec{D}}{\partial t}</math>, to make Ampère's law consistent with conservation of charge in cases where charge is accumulating, for example in a capacitor. He interpreted this as a real motion of charges, even in vacuum, where he supposed that it corresponded to motion of dipole charges in the ether. Although this interpretation has been abandoned, Maxwell's correction to Ampère's law remains valid (a changing electric field produces a magnetic field). Maxwell's equation combining Ampère's law with the displacement current concept is given as <math>\vec{\nabla} \times \vec{H} = \vec{J} + \frac{\partial \vec{D}}{\partial t}</math>. (Integrating both sides, the integral of <math>\vec{\nabla}\times \vec{H}</math> can be replaced — courtesy of Stokes's theorem — with the integral of <math>\vec{H} \cdot \mathrm{d} \vec{l}</math> over a closed contour, thus demonstrating the interconnection with Ampère's formulation.) # Coefficients of Potential The discussion above is limited to the case of two conducting plates, although of arbitrary size and shape. The definition C=Q/V still holds if only one plate is given a charge, provided that we recognize that the field lines produced by that charge terminate as if the plate were at the center of an oppositely charged sphere at infinity. C=Q/V does not apply when there are more than two charged plates, or when the net charge on the two plates is non-zero. To handle this case, Maxwell introduced his "coefficients of potential". If three plates are given charges <math>Q_1, Q_2, Q_3</math>, then the voltage of plate 1 is given by and similarly for the other voltages. Maxwell showed that the coefficients of potential are symmetric, so that <math>p_{12}=p_{21}</math>, etc. # Capacitance/inductance duality In mathematical terms, the ideal capacitance can be considered as an inverse of the ideal inductance, because the voltage-current equations of the two phenomena can be transformed into one another by exchanging the voltage and current terms. # Self-capacitance In electrical circuits, the term capacitance is usually a shorthand for the mutual capacitance between two adjacent conductors, such as the two plates of a capacitor. There also exists a property called self-capacitance, which is the amount of electrical charge that must be added to an isolated conductor to raise its electrical potential by one volt. The reference point for this potential is a theoretical hollow conducting sphere, of infinite radius, centred on the conductor. Using this method, the self-capacitance of a conducting sphere of radius R is given by: Typical values of self-capacitance are: - for the top "plate" of a van de Graaf generator, typically a sphere 20 cm in radius: 20 pF - the planet Earth: about 710 µF # Elastance The inverse of capacitance is called elastance, and its unit is the reciprocal farad, also informally called the daraf. # Stray capacitance Any two adjacent conductors can be considered as a capacitor, although the capacitance will be small unless the conductors are close together or long. This (unwanted) effect is termed "stray capacitance". Stray capacitance can allow signals to leak between otherwise isolated circuits (an effect called crosstalk), and it can be a limiting factor for proper functioning of circuits at high frequency. Stray capacitance is often encountered in amplifier circuits in the form of "feedthrough" capacitance that interconnects the input and output nodes (both defined relative to a common ground). It is often convenient for analytical purposes to replace this capacitance with a combination of one input-to-ground capacitance and one output-to-ground capacitance. (The original configuration — including the input-to-output capacitance — is often referred to as a pi-configuration.) Miller's theorem can be used to effect this replacement. Miller's theorem states that, if the gain ratio of two nodes is 1:K, then an impedance of Z connecting the two nodes can be replaced with a Z/(1-k) impedance between the first node and ground and a KZ/(K-1) impedance between the second node and ground. (Since impedance varies inversely with capacitance, the internode capacitance, C, will be seen to have been replaced by a capacitance of KC from input to ground and a capacitance of (K-1)C/K from output to ground.) When the input-to-output gain is very large, the equivalent input-to-ground impedance is very small while the output-to-ground impedance is essentially equal to the original (input-to-output) impedance. # Capacitors The capacitance of the majority of capacitors used in electronic circuits is several orders of magnitude smaller than the farad. The most common subunits of capacitance in use today are the millifarad (mF), microfarad (µF), the nanofarad (nF) and the picofarad (pF) The capacitance can be calculated if the geometry of the conductors and the dielectric properties of the insulator between the conductors are known. For example, the capacitance of a parallel-plate capacitor constructed of two parallel plates of area A separated by a distance d is approximately equal to the following: where The equation is a good approximation if d is small compared to the other dimensions of the plates. In CGS units the equation has the form: where C in this case has the units of length. The dielectric constant for a number of very useful dielectrics changes as a function of the applied electrical field, e.g. ferroelectric materials, so the capacitance for these devices is no longer purely a function of device geometry. If a capacitor is driven with a sinusoidal voltage, the dielectric constant, or more accurately referred to as the relative static permittivity, is a function of frequency. A changing dielectric constant with frequency is referred to as a dielectric dispersion, and is governed by dielectric relaxation processes, such as Debye relaxation. # Footnotes	https://www.wikidoc.org/index.php/Capacitance
6aab3abd09912a3cc0dbdd512c57d2f2219f4f04	wikidoc	Caprolactam	Caprolactam # Overview Caprolactam is an organic compound which is a cyclic amide (or lactam). The primary industrial use of caprolactam is as a monomer in the production of nylon. Most of the caprolactam is synthesised from cyclohexanoxime by a Beckmann rearrangement. Caprolactam is an irritant and is toxic by ingestion, inhalation, or absorption through the skin. de:Caprolactam it:Caprolattame nl:Caprolactam	Caprolactam Template:Chembox new # Overview Caprolactam is an organic compound which is a cyclic amide (or lactam). The primary industrial use of caprolactam is as a monomer in the production of nylon. Most of the caprolactam is synthesised from cyclohexanoxime by a Beckmann rearrangement. Caprolactam is an irritant and is toxic by ingestion, inhalation, or absorption through the skin. de:Caprolactam it:Caprolattame nl:Caprolactam Template:WS	https://www.wikidoc.org/index.php/Caprolactam
9d86bf8284f0e82cd6c48ca3f8827541e09a1d8c	wikidoc	Carbimazole	Carbimazole Carbimazole is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents the peroxidase enzyme from coupling and iodinating the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine). # Clinical use Therapy for hyperthyroidism generally starts at a high dose of 15 - 40mg continued until the patient has normal thyroid function, and then reduced to a maintenance dose of 5 - 15mg. Treatment is usually given for 12 - 18 months followed by a trial withdraw. The onset of anti-thyroid effect is rapid but the onset of clinical effects on thyroid hormone levels in the blood is much slower. This is because the large store of pre-formed T3 and T4 in the thyroid gland has to be depleted before any beneficial clinical effect occurs. # Side Effects Whilst rashes and pruritus are common, these can often be treated with antihistamines without stopping the carbimazole. For those patients where sensitivity reactions can not be controlled, propylthiouracil may be used as an alternative. Its most serious rare side effect is bone marrow suppression causing neutropenia and agranulocytosis. This may occur at any stage during treatment and without warning. Patients are advised to immediately report symptoms of infection, especially sore throats, so that a full blood count test may be arranged. If this confirms a low neutrophil count then the drug must be discontinued immediately, allowing for usually a prompt recovery. However failure to report suggestive symptoms or delays in considering the possibility of immunosuppresion and its testing, can lead to fatalities.	Carbimazole Carbimazole is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents the peroxidase enzyme from coupling and iodinating the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine). # Clinical use Therapy for hyperthyroidism generally starts at a high dose of 15 - 40mg continued until the patient has normal thyroid function, and then reduced to a maintenance dose of 5 - 15mg. Treatment is usually given for 12 - 18 months followed by a trial withdraw. The onset of anti-thyroid effect is rapid but the onset of clinical effects on thyroid hormone levels in the blood is much slower. This is because the large store of pre-formed T3 and T4 in the thyroid gland has to be depleted before any beneficial clinical effect occurs. # Side Effects Whilst rashes and pruritus are common, these can often be treated with antihistamines without stopping the carbimazole. For those patients where sensitivity reactions can not be controlled, propylthiouracil may be used as an alternative. Its most serious rare side effect is bone marrow suppression causing neutropenia and agranulocytosis. This may occur at any stage during treatment and without warning. Patients are advised to immediately report symptoms of infection, especially sore throats, so that a full blood count test may be arranged. If this confirms a low neutrophil count then the drug must be discontinued immediately, allowing for usually a prompt recovery. However failure to report suggestive symptoms or delays in considering the possibility of immunosuppresion and its testing, can lead to fatalities.	https://www.wikidoc.org/index.php/Carbimazole
d0b46c3e380bbc5f9af4f0b3f5f00d3ed1bd0d98	wikidoc	Mepivacaine	Mepivacaine # 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 Mepivacaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of epidural anesthesia, epidural block, injection of anesthetic agent into brachial plexus, injection of anesthetic agent into pudendal nerve, local anesthesia, local anesthesia, by infiltration, local anesthetic intercostal nerve block. local anesthetic nerve block, transvaginal, local anesthetic nerve block in cervical region. pain management, paracervical block anesthesia, regional anesthesia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cardiovascular: bradyarrhythmia, cardiac arrest, fetal bradycardia, with paracervical block, heart block, hypotension, ventricular arrhythmia, immunologic: bacterial meningitis, septic, immune hypersensitivity reaction (rare ), musculoskeletal: chondrolysis of articular cartilage, neurologic: cranial nerve disorder, seizure, respiratory: respiratory arrest. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosage varies with anesthetic procedure, area to be anesthetized, vascularity of tissues, number of neuronal segments to be blocked, depth of anesthesia and degree of muscle relaxation required, and duration of anesthesia required. - 15 to 30 mL (150 to 300 mg) of 1% solution. - 10 to 25 mL (150 to 375 mg) of 1.5% solution. - 10 to 20 mL (200 to 400 mg) of 2% solution - 5 to 40 mL (50 to 400 mg) of 1% solution - 5 to 20 mL (100 to 400 mg) of 2% solution - 5 to 40 mL (50 to 400 mg) of 1% solution; one-half of total dose injected into each side - 5 to 20 mL (100 to 400 mg) of 2% solution; one-half of total dose injected into each side - Doses vary with anesthetic procedure, MAX single adult dose is 400 mg - Local anesthesia, by infiltration - 0.5% or 1% solution; MAX dose 400 mg - Local anesthetic intercostal nerve block - 5 to 40 mL (50 to 400 mg) of 1% solution - 5 to 20 mL (100 to 400 mg) of 2% solution - Local anesthetic nerve block, Transvaginal - Max 30 mL (300 mg) of 1% solution; one-half of total dose injected into each side - Local anesthetic nerve block in cervical region - 5 to 40 mL (50 to 400 mg) of 1% solution - 5 to 20 mL (100 to 400 mg) of 2% solution - 1 to 5 mL (10 to 50 mg) of 1% solution - 1 to 5 mL (20 to 100 mg) of 2% solution - Max 20 mL (200 mg) of 1% solution every 90 min; one half of total dose injected each side; inject slowly, with 5 min between sides - Doses vary with anesthetic procedure, MAX single adult dose is 400 mg ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Mepivacaine in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Mepivacaine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Mepivacaine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Mepivacaine in pediatric patients. # Contraindications - Mepivacaine is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type or to other components of solutions of Mepivacaine. # Warnings - Local anesthetics should only be employed by clinicians who are well versed in diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. (see also adverse reactions and precautions.) delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. - Local anesthetic solutions containing antimicrobial preservatives (i.e., those supplied in multiple-dose vials) should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentionally or inadvertently, of such preservatives. - Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. - It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection. - Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics. - Mepivacaine with epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of Mepivacaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. - Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. - Mixing or the prior or intercurrent use of any local anesthetic with Mepivacaine cannot be recommended because of insufficient data on the clinical use of such mixtures. # Adverse Reactions ## Clinical Trials Experience - Reactions to Mepivacaine are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, inadvertent intravascular injection, or slow metabolic degradation. - The most commonly encountered acute adverse experiences which demand immediate counter-measures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. - These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. - The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. - High doses or, inadvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension (or sometimes hypertension), bradycardia, ventricular arrhythmias, and possibly cardiac arrest. (See Warnings, Precautions, and Overdosage sections.) - Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben, contained in multiple-dose vials. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. - The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. - In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. - Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control all of which may have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. - Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery. ## Postmarketing Experience There is limited information regarding Mepivacaine Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Mepivacaine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with mepivacaine. There are no adequate and well-controlled studies in pregnant women of the effect of mepivacaine on the developing fetus. Mepivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. This does not preclude the use of Mepivacaine at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.) - Mepivacaine has been used for obstetrical analgesia by the epidural, caudal, and paracervical routes without evidence of adverse effects on the fetus when no more than the maximum safe dosages are used and strict adherence to technique is followed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mepivacaine in women who are pregnant. ### Labor and Delivery - Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See Pharmacokinetics-Clinical Pharmacology.) The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. - Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. - Epidural, paracervical, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. - The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. - Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. Added risk appears to be present in prematurity, postmaturity, toxemia of pregnancy, and fetal distress. The physician should weigh the possible advantages against dangers when considering paracervical block in these conditions. Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. - Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth which correlates with high local anesthetic serum levels and usually manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. - Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a five-minute interval between sides. - It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left. ### Nursing Mothers - It is not known whether local anesthetic drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when local anesthetics are administered to a nursing woman. ### Pediatric Use - Guidelines for the administration of mepivacaine to pediatric patients are presented in Dosage And Administration. ### Geriatic Use - Clinical studies and other reported clinical experience indicates that use of the drug in elderly patients requires a decreased dosage, (see Clinical Pharmacology, Precautions, General, and Dosage and Administration). - Mepivacaine and mepivacaine metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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 There is no FDA guidance on the use of Mepivacaine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mepivacaine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mepivacaine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mepivacaine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mepivacaine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mepivacaine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding drug administration of Mepivacaine in the drug label. ### Monitoring There is limited information regarding drug monitoring of Mepivacaine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Mepivacaine in the drug label. # Overdosage - Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution. (See Adverse reactions, Warnings, and Precautions.) - The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. - The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred. - If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory, and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). - Endotracheal intubation, employing drugs and techniques familiar to the clinician may be indicated after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. - Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. - If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis, plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary. Recovery has been reported after prolonged resuscitative efforts. - The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. - The mean seizure dosage of mepivacaine in rhesus monkeys was found to be 18.8 mg/kg with mean arterial plasma concentration of 24.4 mcg/mL. The intravenous and subcutaneous LD50 in mice is 23 mg/kg to 35 mg/kg and 280 mg/kg respectively. # Pharmacology ## Mechanism of Action - Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. - Clinically, the order of loss of nerve function is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone. ## Structure - Mepivacaine hydrochloride is 2-Piperidinecarboxamide, N-(2,6-dimethylphenyl)-1-methyl, monohydrochloride and has the following structural formula: - It is a white crystalline odorless powder, soluble in water, but very resistant to both acid and alkaline hydrolysis. - Mepivacaine is a local anesthetic available as sterile isotonic solutions (clear, colorless) in concentrations of 1%, 1.5%, and 2% for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. - Mepivacaine hydrochloride is related chemically and pharmacologically to the amide-type local anesthetics. It contains an amide linkage between the aromatic nucleus and the amino group. - In Water for Injection. - The pH of the solution is adjusted between 4.5 and 6.8 with sodium hydroxide or hydrochloric acid. ## Pharmacodynamics - Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. - Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage. - A clinical study using 15 mL of 2% epidural mepivacaine at the T 9-10 interspace in 62 patients, 20-79 years of age, demonstrated a 40% decrease in the amount of mepivacaine required to block a given number of dermatomes in the elderly (60-79 years, N=13) as compared to young adults 20-39 years). - Another study using 10 mL of 2% lumbar epidural mepivacaine in 161 patients, 19-75 years of age, demonstrated a strong inverse relationship between patient age and the number of dermatomes blocked per cc of mepivacaine injected. ## Pharmacokinetics - The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and plasma concentration of Mepivacaine, however, it has been reported that vasoconstrictors do not significantly prolong anesthesia with Mepivacaine. - Onset of anesthesia with Mepivacaine is rapid, the time of onset for sensory block ranging from about 3 to 20 minutes depending upon such factors as the anesthetic technique, the type of block, the concentration of the solution, and the individual patient. The degree of motor blockade produced is dependent on the concentration of the solution. A 0.5% solution will be effective in small superficial nerve blocks while the 1% concentration will block sensory and sympathetic conduction without loss of motor function. The 1.5% solution will provide extensive and often complete motor block and the 2% concentration of Mepivacaine will produce complete sensory and motor block of any nerve group. - The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual. Mepivacaine will normally provide anesthesia which is adequate for 2 to 2 1/2 hours of surgery. - Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma. - Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by the degree of plasma protein binding, the degree of ionization, and the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Mepivacaine is approximately 75% bound to plasma proteins. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. - Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. - Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of Mepivacaine in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 hours. - Mepivacaine, because of its amide structure, is not detoxified by the circulating plasma esterases. It is rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from human adults: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2′ 6′-pipecoloxylidide). - Mepivacaine does not ordinarily produce irritation or tissue damage, and does not cause methemoglobinemia when administered in recommended doses and concentrations. ## Nonclinical Toxicology There is limited information regarding Mepivacaine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Mepivacaine Clinical Studies in the drug label. # How Supplied - Single-dose vials and multiple-dose vials of Mepivacaine may be sterilized by autoclaving at 15 pound pressure, 121°C (250°F) for 15 minutes. Solutions of Mepivacaine may be reautoclaved when necessary. Do not administer solutions which are discolored or which contain particulate matter. - These solutions are not intended for spinal anesthesia or dental use ## Storage - Store at 20 to 25°C (68 to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Mepivacaine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Mepivacaine 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 Mepivacaine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Mepivacaine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Mepivacaine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, 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 Mepivacaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of epidural anesthesia, epidural block, injection of anesthetic agent into brachial plexus, injection of anesthetic agent into pudendal nerve, local anesthesia, local anesthesia, by infiltration, local anesthetic intercostal nerve block. local anesthetic nerve block, transvaginal, local anesthetic nerve block in cervical region. pain management, paracervical block anesthesia, regional anesthesia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cardiovascular: bradyarrhythmia, cardiac arrest, fetal bradycardia, with paracervical block, heart block, hypotension, ventricular arrhythmia, immunologic: bacterial meningitis, septic, immune hypersensitivity reaction (rare ), musculoskeletal: chondrolysis of articular cartilage, neurologic: cranial nerve disorder, seizure, respiratory: respiratory arrest. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosage varies with anesthetic procedure, area to be anesthetized, vascularity of tissues, number of neuronal segments to be blocked, depth of anesthesia and degree of muscle relaxation required, and duration of anesthesia required. - 15 to 30 mL (150 to 300 mg) of 1% solution. - 10 to 25 mL (150 to 375 mg) of 1.5% solution. - 10 to 20 mL (200 to 400 mg) of 2% solution - 5 to 40 mL (50 to 400 mg) of 1% solution - 5 to 20 mL (100 to 400 mg) of 2% solution - 5 to 40 mL (50 to 400 mg) of 1% solution; one-half of total dose injected into each side - 5 to 20 mL (100 to 400 mg) of 2% solution; one-half of total dose injected into each side - Doses vary with anesthetic procedure, MAX single adult dose is 400 mg - Local anesthesia, by infiltration - 0.5% or 1% solution; MAX dose 400 mg - Local anesthetic intercostal nerve block - 5 to 40 mL (50 to 400 mg) of 1% solution - 5 to 20 mL (100 to 400 mg) of 2% solution - Local anesthetic nerve block, Transvaginal - Max 30 mL (300 mg) of 1% solution; one-half of total dose injected into each side - Local anesthetic nerve block in cervical region - 5 to 40 mL (50 to 400 mg) of 1% solution - 5 to 20 mL (100 to 400 mg) of 2% solution - 1 to 5 mL (10 to 50 mg) of 1% solution - 1 to 5 mL (20 to 100 mg) of 2% solution - Max 20 mL (200 mg) of 1% solution every 90 min; one half of total dose injected each side; inject slowly, with 5 min between sides - Doses vary with anesthetic procedure, MAX single adult dose is 400 mg ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Mepivacaine in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Mepivacaine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% - Dose not to exceed 5-6 mg/kg - Age under 3 yr, weight less than 30 pounds use concentrations of 0.5-1.5% ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Mepivacaine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Mepivacaine in pediatric patients. # Contraindications - Mepivacaine is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic agent of the amide-type or to other components of solutions of Mepivacaine. # Warnings - Local anesthetics should only be employed by clinicians who are well versed in diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after insuring the immediate availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies. (see also adverse reactions and precautions.) delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. - Local anesthetic solutions containing antimicrobial preservatives (i.e., those supplied in multiple-dose vials) should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentionally or inadvertently, of such preservatives. - Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. - It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection. - Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics. - Mepivacaine with epinephrine or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of Mepivacaine containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result. - Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the region of the proposed injection. - Mixing or the prior or intercurrent use of any local anesthetic with Mepivacaine cannot be recommended because of insufficient data on the clinical use of such mixtures. # Adverse Reactions ## Clinical Trials Experience - Reactions to Mepivacaine are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, inadvertent intravascular injection, or slow metabolic degradation. - The most commonly encountered acute adverse experiences which demand immediate counter-measures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance. - These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. - The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. - High doses or, inadvertent intravascular injection, may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension (or sometimes hypertension), bradycardia, ventricular arrhythmias, and possibly cardiac arrest. (See Warnings, Precautions, and Overdosage sections.) - Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben, contained in multiple-dose vials. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitely established. - The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. - In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. - Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control all of which may have slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. - Neurologic effects following other procedures or routes of administration may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery. ## Postmarketing Experience There is limited information regarding Mepivacaine Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Mepivacaine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been conducted with mepivacaine. There are no adequate and well-controlled studies in pregnant women of the effect of mepivacaine on the developing fetus. Mepivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. This does not preclude the use of Mepivacaine at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.) - Mepivacaine has been used for obstetrical analgesia by the epidural, caudal, and paracervical routes without evidence of adverse effects on the fetus when no more than the maximum safe dosages are used and strict adherence to technique is followed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mepivacaine in women who are pregnant. ### Labor and Delivery - Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See Pharmacokinetics-Clinical Pharmacology.) The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system, peripheral vascular tone, and cardiac function. - Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable. - Epidural, paracervical, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. - The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. - Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. Added risk appears to be present in prematurity, postmaturity, toxemia of pregnancy, and fetal distress. The physician should weigh the possible advantages against dangers when considering paracervical block in these conditions. Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. - Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth which correlates with high local anesthetic serum levels and usually manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. - Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of the local anesthetic should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a five-minute interval between sides. - It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left. ### Nursing Mothers - It is not known whether local anesthetic drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when local anesthetics are administered to a nursing woman. ### Pediatric Use - Guidelines for the administration of mepivacaine to pediatric patients are presented in Dosage And Administration. ### Geriatic Use - Clinical studies and other reported clinical experience indicates that use of the drug in elderly patients requires a decreased dosage, (see Clinical Pharmacology, Precautions, General, and Dosage and Administration). - Mepivacaine and mepivacaine metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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 There is no FDA guidance on the use of Mepivacaine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Mepivacaine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Mepivacaine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Mepivacaine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Mepivacaine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Mepivacaine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding drug administration of Mepivacaine in the drug label. ### Monitoring There is limited information regarding drug monitoring of Mepivacaine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Mepivacaine in the drug label. # Overdosage - Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution. (See Adverse reactions, Warnings, and Precautions.) - The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. - The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not already occurred. - If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress central nervous system, respiratory, and cardiac function, add to postictal depression and may result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force). - Endotracheal intubation, employing drugs and techniques familiar to the clinician may be indicated after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. - Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. - If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis, plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged period if necessary. Recovery has been reported after prolonged resuscitative efforts. - The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. - The mean seizure dosage of mepivacaine in rhesus monkeys was found to be 18.8 mg/kg with mean arterial plasma concentration of 24.4 mcg/mL. The intravenous and subcutaneous LD50 in mice is 23 mg/kg to 35 mg/kg and 280 mg/kg respectively. # Pharmacology ## Mechanism of Action - Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. - Clinically, the order of loss of nerve function is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone. ## Structure - Mepivacaine hydrochloride is 2-Piperidinecarboxamide, N-(2,6-dimethylphenyl)-1-methyl, monohydrochloride and has the following structural formula: - It is a white crystalline odorless powder, soluble in water, but very resistant to both acid and alkaline hydrolysis. - Mepivacaine is a local anesthetic available as sterile isotonic solutions (clear, colorless) in concentrations of 1%, 1.5%, and 2% for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. - Mepivacaine hydrochloride is related chemically and pharmacologically to the amide-type local anesthetics. It contains an amide linkage between the aromatic nucleus and the amino group. - In Water for Injection. - The pH of the solution is adjusted between 4.5 and 6.8 with sodium hydroxide or hydrochloric acid. ## Pharmacodynamics - Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. - Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage. - A clinical study using 15 mL of 2% epidural mepivacaine at the T 9-10 interspace in 62 patients, 20-79 years of age, demonstrated a 40% decrease in the amount of mepivacaine required to block a given number of dermatomes in the elderly (60-79 years, N=13) as compared to young adults 20-39 years). - Another study using 10 mL of 2% lumbar epidural mepivacaine in 161 patients, 19-75 years of age, demonstrated a strong inverse relationship between patient age and the number of dermatomes blocked per cc of mepivacaine injected. ## Pharmacokinetics - The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and plasma concentration of Mepivacaine, however, it has been reported that vasoconstrictors do not significantly prolong anesthesia with Mepivacaine. - Onset of anesthesia with Mepivacaine is rapid, the time of onset for sensory block ranging from about 3 to 20 minutes depending upon such factors as the anesthetic technique, the type of block, the concentration of the solution, and the individual patient. The degree of motor blockade produced is dependent on the concentration of the solution. A 0.5% solution will be effective in small superficial nerve blocks while the 1% concentration will block sensory and sympathetic conduction without loss of motor function. The 1.5% solution will provide extensive and often complete motor block and the 2% concentration of Mepivacaine will produce complete sensory and motor block of any nerve group. - The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual. Mepivacaine will normally provide anesthesia which is adequate for 2 to 2 1/2 hours of surgery. - Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma. - Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by the degree of plasma protein binding, the degree of ionization, and the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Mepivacaine is approximately 75% bound to plasma proteins. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. - Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. - Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of Mepivacaine in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 hours. - Mepivacaine, because of its amide structure, is not detoxified by the circulating plasma esterases. It is rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from human adults: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2′ 6′-pipecoloxylidide). - Mepivacaine does not ordinarily produce irritation or tissue damage, and does not cause methemoglobinemia when administered in recommended doses and concentrations. ## Nonclinical Toxicology There is limited information regarding Mepivacaine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Mepivacaine Clinical Studies in the drug label. # How Supplied - Single-dose vials and multiple-dose vials of Mepivacaine may be sterilized by autoclaving at 15 pound pressure, 121°C (250°F) for 15 minutes. Solutions of Mepivacaine may be reautoclaved when necessary. Do not administer solutions which are discolored or which contain particulate matter. - These solutions are not intended for spinal anesthesia or dental use ## Storage - Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Mepivacaine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Mepivacaine 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 Mepivacaine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Mepivacaine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Carbocaine
ea3e01364cbc308386ed2f1297ba859328c5a61b	wikidoc	Carbocation	Carbocation A carbocation (IPA pronunciation: Template:IPA) is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability (octet rule). Therefore carbocations are often reactive, seeking to fill the octet of valence electrons as well as regain a neutral charge. A typical carbocation has sp2 hybridization with a trigonal planar molecular geometry. # Definitions A carbocation was previously often called a carbonium ion but questions arose on the exact meaning . In present day chemistry a carbocation is any positively charged carbon atom. Two special types have been suggested: carbenium ions are trivalent and carbonium ions are pentavalent or hexavalent. University level textbooks only discuss carbocations as if they are carbenium ions , or discuss carbocations with a fleeting reference to the older phrase of carbonium ion or carbenium and carbonium ions . One textbook to this day clings on to the older name of carbonium ion for carbenium ion and reserves the phrase hypervalent carbenium ion for CH5+ . # History The history of carbocations dates back to 1891 when G. Merling reported that he added bromine to tropylidene (cycloheptatriene) and then heated the product to obtain a crystalline, water soluble material, C7H7Br. He did not suggest a structure for it; however Doering and Knox convincingly showed that it was tropylium (cycloheptatrienylium) bromide. This ion is predicted to be aromatic by the Hückel Rule. In 1902 Norris and Kehrman independently discovered that colorless triphenylmethanol gave deep yellow solutions in concentrated sulfuric acid. Triphenylmethyl chloride similarly formed orange complexes with aluminium and tin chlorides. Adolf von Baeyer recognized in 1902 the salt like character of the compounds formed. He dubbed the relationship between color and salt formation halochromy of which malachite green is a prime example. Carbocations are reactive intermediates in many organic reactions. This idea, first proposed by Julius Stieglitz in 1899 (On the Constitution of the Salts of Imido-Ethers and other Carbimide Derivatives; Am. Chem. J. 21, 101; ISSN: 0096-4085) was further developed by Hans Meerwein in his 1922 study of the Wagner-Meerwein rearrangement. Carbocations were also found to be involved in the SN1 reaction and E1 reaction and in rearrangement reactions such as the Whitmore 1,2 shift. The chemical establishment was reluctant to accept the notion of a carbocation and for a long time the Journal of the American Chemical Society refused articles that mentioned them. The first NMR spectrum of a stable carbocation in solution was published by Doering et al. . It was the heptamethylbenzenonium ion, made by treating hexamethylbenzene with methyl chloride and aluminium chloride. The stable 7-norbornadienyl cation was prepared by Story et al. by reacting norbornadienyl chloride with silver tetrafluoroborate in sulfur dioxide at -80°C . The NMR spectrum established that it was nonclassically bridged (the first stable non-classical ion observed). In 1962 Olah directly observed the tert-butyl carbocation by Nuclear magnetic resonance as a stable species on dissolving tert-butyl fluoride in magic acid. The NMR of norbornyl cation was first reported by Schleyer et al. and it was shown to undergo proton scrambling over a barrier by Saunders et al. . # Properties In organic chemistry, a carbocation is often the target of nucleophilic attack by nucleophiles like OH- ions or halogen ions. Carbocations are classified as primary, secondary, or tertiary depending on the number of carbon atoms bonded to the ionized carbon. Primary carbocations have one or zero carbons attached to the ionized carbon, secondary carbocations have two carbons attached to the ionized carbon, and tertiary carbocations have three carbons attached to the ionized carbon. Stability of the carbocation increases with the number of alkyl groups bonded to the charge-bearing carbon. Tertiary carbocations are more stable (and form more readily) than secondary carbocations; primary carbocations are highly unstable because, while ionized higher-order carbons are stabilized by Hyperconjugation, unsubstituted (primary) carbons are not. Therefore, reactions such as the SN1 reaction and the E1 elimination reaction normally do not occur if a primary carbocation would be formed. An exception to this occurs when there is a carbon-carbon double bond next to the ionized carbon. Such cations as allyl cation CH2=CH-CH2+ and benzyl cation C6H5-CH2+ are more stable than most other carbocations. Molecules which can form allyl or benzyl carbocations are especially reactive. Carbocations undergo rearrangement reactions from less stable structures to equally stable or more stable ones with rate constants in excess of 1.0E9/sec. This fact complicates synthetic pathways to many compounds. For example, when 3-pentanol is heated with aqueous HCl, the initially formed 3-pentyl carbocation rearranges to a statistical mixture of the 3-pentyl and 2-pentyl. These cations react with chloride ion to produce about 1/3 3-chloropentane and 2/3 2-chloropentane. Some carbocations such as the norbornyl cation exhibit more or less symmetrical three centre bonding. Cations of this sort have been referred to as non-classical ions. The energy difference between "classical" carbocations and "non-classical" isomers is often very small, and there is generally little, if any activation energy involved in the transition between "classical" and "non-classical" structures. The "non-classical" form of the 2-butyl carbocation is essentially 2-butene with a proton directly above the centre of what would be the carbon-carbon double bond. "Non-classical" carbocations were once the subject of great controversy. One of George Olah's greatest contributions to chemistry was resolving this controversy .	Carbocation A carbocation (IPA pronunciation: Template:IPA) is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability (octet rule). Therefore carbocations are often reactive, seeking to fill the octet of valence electrons as well as regain a neutral charge. A typical carbocation has sp2 hybridization with a trigonal planar molecular geometry. # Definitions A carbocation was previously often called a carbonium ion but questions arose on the exact meaning [1]. In present day chemistry a carbocation is any positively charged carbon atom. Two special types have been suggested: carbenium ions are trivalent and carbonium ions are pentavalent or hexavalent. University level textbooks only discuss carbocations as if they are carbenium ions [2], or discuss carbocations with a fleeting reference to the older phrase of carbonium ion [3] or carbenium and carbonium ions [4]. One textbook to this day clings on to the older name of carbonium ion for carbenium ion and reserves the phrase hypervalent carbenium ion for CH5+ [5]. # History The history of carbocations dates back to 1891 when G. Merling [6] reported that he added bromine to tropylidene (cycloheptatriene) and then heated the product to obtain a crystalline, water soluble material, C7H7Br. He did not suggest a structure for it; however Doering and Knox [7] convincingly showed that it was tropylium (cycloheptatrienylium) bromide. This ion is predicted to be aromatic by the Hückel Rule. In 1902 Norris and Kehrman independently discovered that colorless triphenylmethanol gave deep yellow solutions in concentrated sulfuric acid. Triphenylmethyl chloride similarly formed orange complexes with aluminium and tin chlorides. Adolf von Baeyer recognized in 1902 the salt like character of the compounds formed. He dubbed the relationship between color and salt formation halochromy of which malachite green is a prime example. Carbocations are reactive intermediates in many organic reactions. This idea, first proposed by Julius Stieglitz in 1899 (On the Constitution of the Salts of Imido-Ethers and other Carbimide Derivatives; Am. Chem. J. 21, 101; ISSN: 0096-4085) was further developed by Hans Meerwein in his 1922 study [8] of the Wagner-Meerwein rearrangement. Carbocations were also found to be involved in the SN1 reaction and E1 reaction and in rearrangement reactions such as the Whitmore 1,2 shift. The chemical establishment was reluctant to accept the notion of a carbocation and for a long time the Journal of the American Chemical Society refused articles that mentioned them. The first NMR spectrum of a stable carbocation in solution was published by Doering et al. [9]. It was the heptamethylbenzenonium ion, made by treating hexamethylbenzene with methyl chloride and aluminium chloride. The stable 7-norbornadienyl cation was prepared by Story et al. [10] by reacting norbornadienyl chloride with silver tetrafluoroborate in sulfur dioxide at -80°C . The NMR spectrum established that it was nonclassically bridged (the first stable non-classical ion observed). In 1962 Olah directly observed the tert-butyl carbocation by Nuclear magnetic resonance as a stable species on dissolving tert-butyl fluoride in magic acid. The NMR of norbornyl cation was first reported by Schleyer et al. [11] and it was shown to undergo proton scrambling over a barrier by Saunders et al. [12]. # Properties In organic chemistry, a carbocation is often the target of nucleophilic attack by nucleophiles like OH- ions or halogen ions. Carbocations are classified as primary, secondary, or tertiary depending on the number of carbon atoms bonded to the ionized carbon. Primary carbocations have one or zero carbons attached to the ionized carbon, secondary carbocations have two carbons attached to the ionized carbon, and tertiary carbocations have three carbons attached to the ionized carbon. Stability of the carbocation increases with the number of alkyl groups bonded to the charge-bearing carbon. Tertiary carbocations are more stable (and form more readily) than secondary carbocations; primary carbocations are highly unstable because, while ionized higher-order carbons are stabilized by Hyperconjugation, unsubstituted (primary) carbons are not. Therefore, reactions such as the SN1 reaction and the E1 elimination reaction normally do not occur if a primary carbocation would be formed. An exception to this occurs when there is a carbon-carbon double bond next to the ionized carbon. Such cations as allyl cation CH2=CH-CH2+ and benzyl cation C6H5-CH2+ are more stable than most other carbocations. Molecules which can form allyl or benzyl carbocations are especially reactive. Carbocations undergo rearrangement reactions from less stable structures to equally stable or more stable ones with rate constants in excess of 1.0E9/sec. This fact complicates synthetic pathways to many compounds. For example, when 3-pentanol is heated with aqueous HCl, the initially formed 3-pentyl carbocation rearranges to a statistical mixture of the 3-pentyl and 2-pentyl. These cations react with chloride ion to produce about 1/3 3-chloropentane and 2/3 2-chloropentane. Some carbocations such as the norbornyl cation exhibit more or less symmetrical three centre bonding. Cations of this sort have been referred to as non-classical ions. The energy difference between "classical" carbocations and "non-classical" isomers is often very small, and there is generally little, if any activation energy involved in the transition between "classical" and "non-classical" structures. The "non-classical" form of the 2-butyl carbocation is essentially 2-butene with a proton directly above the centre of what would be the carbon-carbon double bond. "Non-classical" carbocations were once the subject of great controversy. One of George Olah's greatest contributions to chemistry was resolving this controversy [13].	https://www.wikidoc.org/index.php/Carbocation
780bd740adb2b60a11633cb9a7ca5acc25669a4f	wikidoc	Carboplatin	Carboplatin # 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 Carboplatin is an antineoplastic agent that is FDA approved for the treatment of advanced ovarian carcinoma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, abdominal pain, diarrhea, nausea, vomiting, anemia, leukopenia, neutropenia, thrombocytopenia, pain, and elevation of alkaline phosphatase, AST, BUN, and creatinine. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Carboplatin Injection is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. One established combination regimen consists of Carboplatin Injection and cyclophosphamide. Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin vs. cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups - There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival (≥3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor <2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup. - Carboplatin Injection is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin. - Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate. ### Dosage NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of Carboplatin Injection. - Carboplatin Injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of Carboplatin Injection should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000. - In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of: - Carboplatin Injection - 300 mg/m2 IV on day 1 every four weeks for six cycles (alternatively see Formula Dosing). - Cyclophosphamide - 600 mg/m2 IV on day 1 every four weeks for six cycles. For directions regarding the use and administration of cyclophosphamide . - Intermittent courses of Carboplatin Injection in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000. - Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients. - The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value. - Carboplatin Injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or hydrationpost-treatment hydration or forced diuresis is required. - Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single-agent Carboplatin Injection therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used. - The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment. - These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient’s tolerance based on the degree of bone marrow suppression. - Another approach for determining the initial dose of Carboplatin Injection is the use of mathematical formulae, which are based on a patient’s preexisting renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin. The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function). - A simple formula for calculating dosage, based upon a patient’s glomerular filtration rate (GFR in mL/min) and Carboplatin Injection target area under the concentration versus time curve (AUC in mg/mLmin), has been proposed by Calvert. In these studies, GFR was measured by 51Cr-EDTA clearance. - Because renal function is often decreased in elderly patients, formula dosing of Carboplatin Injection based on estimates of GFR should be used in elderly patients to provide predictable plasma Carboplatin Injection AUCs and thereby minimize the risk of toxicity. - Carboplatin Injection 10 mg/mL is supplied as a Ready To Use (RTU) sterile solution in 5 mL, 15 mL, 45 mL or 60 mL vials. Total content of carboplatin per vial is described in following table: - Carboplatin Injection can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. - When further diluted, Carboplatin Injection solutions are stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is recommended that Carboplatin Injection solutions be discarded 8 hours after dilution. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Gemcitabine 1000 mg/m(2) IV over 30 minutes on days 1 and 8 plus carboplatin (AUC 5.5) IV over 15 to 30 min on day 1 OR paclitaxel 225 mg/m(2) IV over 3 hours on day 1 plus carboplatin (AUC 6) IV over 15 to 30 minutes on day 1 OR plus gemcitabine 1000 mg/m(2) IV over 30 minutes on days 1 and 8 pluspaclitaxel 200 mg/m(2) IV over 3 hours on day 1; repeated every 21 days for 6 cycles or until unacceptable toxicity or disease progression was used in a phase 3 randomized trial - Carboplatin (AUC of 6) IV, paclitaxel 200 mg/m(2) IV, and bevacizumab 15 mg/kg IV once on day 1 every 3 weeks for up to 6 cycles, then bevacizumab alone until disease progression has been studied in clinical trials ### Non–Guideline-Supported Use - CARBOPLATIN (AUC=6 IV day 1) repeated every 3 weeks. - Carboplatin 400 mg/m(2) (340 mg/m(2) if the patient had prior radiotherapy) was administered IV over 15 minutes and doses repeated every 4 weeks. - IV carboplatin 100 mg/m(2). - carboplatin is used in combination with ifosfamide and etoposide for Hodgkin disease - Dosage - Carboplatin IV 150 mg/m(2)/day for 3 days. - ICE regimen: etoposide 100 mg/m(2) IV bolus on days 1 to 3, carboplatin AUC 5 IV bolus on day 2 (MAX dose 800 mg), ifosfamide 5 g/m(2) admixed with mesna 5 g/m(2) via IV continuous infusion over 24 hours on day 2; repeat every 14 days for 3 cycles; filgrastim 5 mcg/kg/day on days 5 to 12 of cycle 1 and 2, and filgrastim 10 mcg/kg/day after cycle 3 until the end of leukapheresis - AUC 7 IV for 1 course was used in a clinical trial - AUC 7 IV every 21 days for 2 courses was used in high-risk patients (tumor larger than 4 cm or invasion of the rete testis) in a clinical trial # 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 - Carboplatin injection is contraindicated in patients with a history of severe allergic reactions to cisplatin or other platinum-containing compounds. - Carboplatin should not be employed in patients with severe bone marrow depression or significant bleeding. # Warnings - Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts should be frequently monitored during carboplatin treatment and, when appropriate, until recovery is achieved. Median nadir occurs at day 21 in patients receiving single-agent carboplatin. In general, single intermittent courses of carboplatin should not be repeated until leukocyte, neutrophil, and platelet counts have recovered. - Since anemia is cumulative, transfusions may be needed during treatment with carboplatin, particularly in patients receiving prolonged therapy. - Bone marrow suppression is increased in patients who have received prior therapy, especially regimens including cisplatin. Marrow suppression is also increased in patients with impaired kidney function. Initial carboplatin dosages in these patients should be appropriately reduced and blood counts should be carefully monitored between courses. The use of carboplatin in combination with other bone marrow suppressing therapies must be carefully managed with respect to dosage and timing in order to minimize additive effects. - Carboplatin has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution must be exercised when a patient receives both drugs. Clinically significant hearing loss has been reported to occur in pediatric patients when carboplatin was administered at higher than recommended doses in combination with other ototoxic agents. - Carboplatin can induce emesis, which can be more severe in patients previously receiving emetogenic therapy. The incidence and intensity of emesis have been reduced by using premedication with antiemetics. Although no conclusive efficacy data exist with the following schedules of carboplatin, lengthening the duration of single intravenous administration to 24 hours or dividing the total dose over 5 consecutive daily pulse doses has resulted in reduced emesis. - Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 65 years and in patients previously treated with cisplatin. Pre-existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients receiving carboplatin as secondary treatment. - Loss of vision, which can be complete for light and colors, has been reported after the use of carboplatin with doses higher than those recommended in the package insert. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses. - As in the case of other platinum-coordination compounds, allergic reactions to carboplatin have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy. There is increased risk of allergic reactions including anaphylaxis in patients previously exposed to platinum therapy. - High dosages of carboplatin (more than 4 times the recommended dose) have resulted in severe abnormalities of liver function tests. - Carboplatin injection may cause fetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats. There are no adequate and well-controlled studies in pregnant women. 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. Women of childbearing potential should be advised to avoid becoming pregnant. ### Precautions - General - Needles or intravenous administration sets containing aluminum parts that may come in contact with Carboplatin injection should not be used for the preparation or administration of the drug. Aluminum can react with carboplatin causing precipitate formation and loss of potency. # Adverse Reactions ## Clinical Trials Experience - For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide - Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer - Data are based on the experience of 393 patients with ovarian cancer (regardless of baseline status) who received initial combination therapy with carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC . - Combination with cyclophosphamide as well as duration of treatment may be responsible for the differences that can be noted in the adverse experience table. - Single Agent Use for the Secondary Treatment of Ovarian Cancer - Data are based on the experience of 553 patients with previously treated ovarian carcinoma (regardless of baseline status) who received single-agent carboplatin - In the narrative section that follows, the incidences of adverse events are based on data from 1,893 patients with various types of tumors who received carboplatin as single-agent therapy. - Hematologic Toxicity - Bone marrow suppression is the dose-limiting toxicity of carboplatin. :*Thrombocytopenia with platelet counts below 50,000/mm3 occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm3 occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm3 occurs in 15% of the patients (26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in patients receiving single-agent therapy. By day 28, 90% of patients have platelet counts above 100,000/mm3; 74% have neutrophil counts above 2,000/mm3; 67% have leukocyte counts above 4,000/mm3. - Marrow suppression is usually more severe in patients with impaired kidney function. Patients with poor performance status have also experienced a higher incidence of severe leukopenia and thrombocytopenia. - The hematologic effects, although usually reversible, have resulted in infectious or hemorrhagic complications in 5% of the patients treated with carboplatin, with drug-related death occurring in less than 1% of the patients. Fever has also been reported in patients with neutropenia. - Anemia with hemoglobin less than 11 g/dL has been observed in 71% of the patients who started therapy with a baseline above that value. The incidence of anemia increases with increasing exposure to carboplatin. Transfusions have been administered to 26% of the patients treated with carboplatin (44% of previously treated ovarian cancer patients). - Bone marrow depression may be more severe when carboplatin is combined with other bone marrow suppressing drugs or with radiotherapy. - Gastrointestinal Toxicity - Vomiting occurs in 65% of the patients (81% of previously treated ovarian cancer patients) and in about one-third of these patients it is severe. Carboplatin, as a single agent or in combination, is significantly less emetogenic than cisplatin; however, patients previously treated with emetogenic agents, especially cisplatin, appear to be more prone to vomiting. Nausea alone occurs in an additional 10 to 15% of patients. Both nausea and vomiting usually cease within 24 hours of treatment and are often responsive to antiemetic measures. Although no conclusive efficacy data exist with the following schedules, prolonged administration of carboplatin, either by continuous 24-hour infusion or by daily pulse doses given for 5 consecutive days, was associated with less severe vomiting than the single-dose intermittent schedule. Emesis was increased when carboplatin was used in combination with other emetogenic compounds. Other gastrointestinal effects observed frequently were pain, in 17% of the patients; diarrhea, in 6%; and constipation, also in 6%. - Neurologic Toxicity - Peripheral neuropathies have been observed in 4% of the patients receiving carboplatin (6% of pretreated ovarian cancer patients) with mild paresthesias occurring most frequently. Carboplatin therapy produces significantly fewer and less severe neurologic side effects than does therapy with cisplatin. However, patients older than 65 years and/or previously treated with cisplatin appear to have an increased risk (10%) for peripheral neuropathies. In 70% of the patients with pre-existing cisplatin-induced peripheral neurotoxicity, there was no worsening of symptoms during therapy with carboplatin. Clinical ototoxicity and other sensory abnormalities such as visual disturbances and change in taste have been reported in only 1% of the patients. Central nervous system symptoms have been reported in 5% of the patients and appear to be most often related to the use of antiemetics. - Although the overall incidence of peripheral neurologic side effects induced by carboplatin is low, prolonged treatment, particularly in cisplatin pretreated patients, may result in cumulative neurotoxicity. - Nephrotoxicity - Development of abnormal renal function test results is uncommon, despite the fact that carboplatin, unlike cisplatin, has usually been administered without high-volume fluid hydration and/or forced diuresis. The incidences of abnormal renal function tests reported are 6% for serum creatinine and 14% for blood urea nitrogen (10% and 22%, respectively, in pretreated ovarian cancer patients). Most of these reported abnormalities have been mild and about one-half of them were reversible. - Creatinine clearance has proven to be the most sensitive measure of kidney function in patients receiving carboplatin, and it appears to be the most useful test for correlating drug clearance and bone marrow suppression. Twenty-seven percent of the patients who had a baseline value of 60 mL/min or more demonstrated a reduction below this value during carboplatin therapy. - Hepatic Toxicity - The incidences of abnormal liver function tests in patients with normal baseline values were reported as follows:total bilirubin, 5%; SGOT, 15%; and alkaline phosphatase, 24%; (5%, 19%, and 37%, respectively, in pretreated ovarian cancer patients). These abnormalities have generally been mild and reversible in about one-half of the cases, although the role of metastatic tumor in the liver may complicate the assessment in many patients. In a limited series of patients receiving very high dosages of carboplatin and autologous bone marrow transplantation, severe abnormalities of liver function tests were reported. - Electrolyte Changes - The incidences of abnormally decreased serum electrolyte values reported were as follows: sodium, 29%; potassium, 20%; calcium, 22%; and magnesium, 29%; (47%, 28%, 31%, and 43%, respectively, in pretreated ovarian cancer patients). Electrolyte supplementation was not routinely administered concomitantly with carboplatin, and these electrolyte abnormalities were rarely associated with symptoms. - Allergic Reactions - Hypersensitivity to carboplatin has been reported in 2% of the patients. These allergic reactions have been similar in nature and severity to those reported with other platinum-containing compounds, i.e, rash, urticaria, erythema,pruritus, and rarely bronchospasm and hypotension. Anaphylactic reactions have been reported as part of postmarketing surveillance . These reactions have been successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy. - Injection Site Reactions - Injection site reactions, including redness, swelling, and pain, have been reported during postmarketing surveillance. Necrosis associated with extravasation has also been reported. - Other Events - Pain and asthenia were the most frequently reported miscellaneous adverse effects; their relationship to the tumor and to anemia was likely. Alopecia was reported (3%). Cardiovascular, respiratory, genitourinary, and mucosal side effects have occurred in 6% or less of the patients. Cardiovascular events (cardiac failure, embolism, cerebrovascular accidents) were fatal in less than 1% of the patients and did not appear to be related to chemotherapy. Cancer-associated hemolytic uremic syndrome has been reported rarely. ## Postmarketing Experience - Malaise, anorexia, hypertension, dehydration, and stomatitis have been reported as part of post marketing surveillance. # Drug Interactions - The renal effects of nephrotoxic compounds may be potentiated by carboplatin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carboplatin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carboplatin during labor and delivery. ### Nursing Mothers Carcinogenesis, Mutagenesis, Impairment of Fertility - The carcinogenic potential of carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established . ### Geriatic Use - Of the 789 patients in initial treatment combination therapy studies (NCIC and SWOG), 395 patients were treated with carboplatin in combination with cyclophosphamide. Of these, 141 were over 65 years of age and 22 were 75 years or older. In these trials, age was not a prognostic factor for survival. In terms of safety, elderly patients treated with carboplatin were more likely to develop severe thrombocytopenia than younger patients. In a combined database of 1,942 patients (414 were ≥65 years of age) that received single-agent carboplatin for different tumor types, a similar incidence of adverse events was seen in patients 65 years and older and in patients less than 65. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because renal function is often decreased in the elderly, renal function should be considered in the selection of carboplatin dosage . ### Gender There is no FDA guidance on the use of Carboplatin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carboplatin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Carboplatin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Carboplatin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carboplatin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carboplatin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Peripheral blood counts should be frequently monitored during carboplatin treatment and, when appropriate, until recovery is achieved. # IV Compatibility - Carboplatin injection is a premixed aqueous solution of 10 mg/mL carboplatin. - Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. - When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at room temperature (25° C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin aqueous solutions be discarded 8 hours after dilution. # Overdosage ## Acute Overdose - The anticipated complications of overdosage would be secondary to bone marrow suppression and/or hepatic toxicity. ### Management - There is no known antidote for Carboplatin injection overdosage. # Pharmacology ## Mechanism of Action - Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, which is thought to produce the active species, occurs at a slower rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological effects. The differences in potencies for carboplatin and cisplatin appear to be directly related to the difference in aquation rates. ## Structure - Carboplatin Injection is for intravenous administration. Each mL contains equivalent to 10 mg of carboplatin in Water for Injection. No other preservatives or additives are present. Carboplatin injection is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution of carboplatin. Carboplatin is a platinum coordination compound. The chemical name for carboplatin is platinum, diammine -,(SP-4-2), and carboplatin has the following structural formula: - Carboplatin is a crystalline powder with the molecular formula of C6H12N2O4Pt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5-7. It is sparingly soluble in water, very slightly soluble in acetone and in alcohol. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Carboplatin in the drug label. ## Pharmacokinetics - In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 300 mg/m2 to 500 mg/m2 of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n=6), and the postdistribution plasma half-life (beta) was found to be 2.6 to 5.9 hours (n=6). The total body clearance, apparent volume of distribution and mean residence time for carboplatin are 4.4 L/hour, 16 L and 3.5 hours, respectively. The Cmax values and areas under the plasma concentration versus time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 mg/m2 to 500 mg/m2). - Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carboplatin are present in plasma. However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days. - The major route of elimination of carboplatin is renal excretion. Patients with creatinine clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour urine is present as carboplatin. Only 3% to 5% of the administered platinum is excreted in the urine between 24 and 96 hours. There are insufficient data to determine whether biliary excretion occurs. - In patients with creatinine clearances below 60 mL/min the total body and renal clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin dosages should therefore be reduced in these patients . - The primary determinant of carboplatin clearance is glomerular filtration rate (GFR) and this parameter of renal function is often decreased in elderly patients. Dosing formulas incorporating estimates of GFR to provide predictable carboplatin plasma AUCs should be used in elderly patients to minimize the risk of toxicity. ## Nonclinical Toxicology - The carcinogenic potential of carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy. # Clinical Studies - In two prospectively randomized, controlled studies conducted by the National Cancer Institute of Canada, Clinical Trials Group (NCIC) and the Southwest Oncology Group (SWOG), 789 chemotherapy naive patients with advanced ovarian cancer were treated with carboplatin or cisplatin, both in combination with cyclophosphamide every 28 days for 6 courses before surgical reevaluation. The following results were obtained from both studies: - The pattern of toxicity exerted by the carboplatin-containing regimen was significantly different from that of the cisplatin-containing combinations. Differences between the two studies may be explained by different cisplatin dosages and by different supportive care. - The carboplatin-containing regimen induced significantly more thrombocytopenia and, in one study, significantly more leukopenia and more need for transfusional support. The cisplatin-containing regimen produced significantly more anemia in one study. However, no significant differences occurred in incidences of infections and hemorrhagic episodes. - Non-hematologic toxicities (emesis, neurotoxicity, ototoxicity, renal toxicity, hypomagnesemia, and alopecia) were significantly more frequent in the cisplatin-containing arms. - In two prospective, randomized controlled studies in patients with advanced ovarian cancer previously treated with chemotherapy, carboplatin achieved 6 clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71 +weeks. # How Supplied - Carboplatin injection - NDC 67457-491-54 50 mg/5 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned. - NDC 67457-492-15 150 mg/15 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned. - NDC 67457-493-46 450 mg/45 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned. - NDC 67457-494-61 600 mg/60 mL aqueous solution in multidose vials (with blue flip-off seals), individually cartoned. - Storage - Unopened vials of carboplatin injection are stable to the date indicated on the package when stored at 20° - 25° C (68° to 77° F) . Protect from light. - Carboplatin injection multidose vials maintain microbial, chemical, and physical stability for up to 14 days at 25° C following multiple needle entries. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Solutions for infusion should be discarded 8 hours after preparation. - Handling and Disposal - Caution should be exercised in handling and preparing carboplatin injection. Several guidelines on this subject have been published.1-4 - To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing carboplatin injection. If carboplatin injection contacts the skin, immediately wash the skin thoroughly with soap and water. If carboplatin injection contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below. ## Storage There is limited information regarding Carboplatin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Carboplatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Paraplatin® - Paraplatin NovaPlus® # Look-Alike Drug Names - CARBOplatin® — CISplatin® # Drug Shortage Status # Price	Carboplatin 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. # Black Box Warning # Overview Carboplatin is an antineoplastic agent that is FDA approved for the treatment of advanced ovarian carcinoma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, abdominal pain, diarrhea, nausea, vomiting, anemia, leukopenia, neutropenia, thrombocytopenia, pain, and elevation of alkaline phosphatase, AST, BUN, and creatinine. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Carboplatin Injection is indicated for the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. One established combination regimen consists of Carboplatin Injection and cyclophosphamide. Two randomized controlled studies conducted by the NCIC and SWOG with carboplatin vs. cisplatin, both in combination with cyclophosphamide, have demonstrated equivalent overall survival between the two groups - There is limited statistical power to demonstrate equivalence in overall pathologic complete response rates and long-term survival (≥3 years) because of the small number of patients with these outcomes: the small number of patients with residual tumor <2 cm after initial surgery also limits the statistical power to demonstrate equivalence in this subgroup. - Carboplatin Injection is indicated for the palliative treatment of patients with ovarian carcinoma recurrent after prior chemotherapy, including patients who have been previously treated with cisplatin. - Within the group of patients previously treated with cisplatin, those who have developed progressive disease while receiving cisplatin therapy may have a decreased response rate. ### Dosage NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of Carboplatin Injection. - Carboplatin Injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of Carboplatin Injection should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000. - In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of: - Carboplatin Injection - 300 mg/m2 IV on day 1 every four weeks for six cycles (alternatively see Formula Dosing). - Cyclophosphamide - 600 mg/m2 IV on day 1 every four weeks for six cycles. For directions regarding the use and administration of cyclophosphamide . - Intermittent courses of Carboplatin Injection in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000. - Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients. - The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value. - Carboplatin Injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or hydrationpost-treatment hydration or forced diuresis is required. - Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single-agent Carboplatin Injection therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used. - The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment. - These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient’s tolerance based on the degree of bone marrow suppression. - Another approach for determining the initial dose of Carboplatin Injection is the use of mathematical formulae, which are based on a patient’s preexisting renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin. The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function). - A simple formula for calculating dosage, based upon a patient’s glomerular filtration rate (GFR in mL/min) and Carboplatin Injection target area under the concentration versus time curve (AUC in mg/mL•min), has been proposed by Calvert. In these studies, GFR was measured by 51Cr-EDTA clearance. - Because renal function is often decreased in elderly patients, formula dosing of Carboplatin Injection based on estimates of GFR should be used in elderly patients to provide predictable plasma Carboplatin Injection AUCs and thereby minimize the risk of toxicity. - Carboplatin Injection 10 mg/mL is supplied as a Ready To Use (RTU) sterile solution in 5 mL, 15 mL, 45 mL or 60 mL vials. Total content of carboplatin per vial is described in following table: - Carboplatin Injection can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. - When further diluted, Carboplatin Injection solutions are stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is contained in the formulation, it is recommended that Carboplatin Injection solutions be discarded 8 hours after dilution. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Gemcitabine 1000 mg/m(2) IV over 30 minutes on days 1 and 8 plus carboplatin (AUC 5.5) IV over 15 to 30 min on day 1 OR paclitaxel 225 mg/m(2) IV over 3 hours on day 1 plus carboplatin (AUC 6) IV over 15 to 30 minutes on day 1 OR plus gemcitabine 1000 mg/m(2) IV over 30 minutes on days 1 and 8 pluspaclitaxel 200 mg/m(2) IV over 3 hours on day 1; repeated every 21 days for 6 cycles or until unacceptable toxicity or disease progression was used in a phase 3 randomized trial - Carboplatin (AUC of 6) IV, paclitaxel 200 mg/m(2) IV, and bevacizumab 15 mg/kg IV once on day 1 every 3 weeks for up to 6 cycles, then bevacizumab alone until disease progression has been studied in clinical trials ### Non–Guideline-Supported Use - CARBOPLATIN (AUC=6 IV day 1) repeated every 3 weeks.[1] - Carboplatin 400 mg/m(2) (340 mg/m(2) if the patient had prior radiotherapy) was administered IV over 15 minutes and doses repeated every 4 weeks.[2] - IV carboplatin 100 mg/m(2).[3] - carboplatin is used in combination with ifosfamide and etoposide for Hodgkin disease [4] - Dosage - Carboplatin IV 150 mg/m(2)/day for 3 days.[5] - ICE regimen: etoposide 100 mg/m(2) IV bolus on days 1 to 3, carboplatin AUC 5 IV bolus on day 2 (MAX dose 800 mg), ifosfamide 5 g/m(2) admixed with mesna 5 g/m(2) via IV continuous infusion over 24 hours on day 2; repeat every 14 days for 3 cycles; filgrastim 5 mcg/kg/day on days 5 to 12 of cycle 1 and 2, and filgrastim 10 mcg/kg/day after cycle 3 until the end of leukapheresis[6] - AUC 7 IV for 1 course was used in a clinical trial[7] - AUC 7 IV every 21 days for 2 courses was used in high-risk patients (tumor larger than 4 cm or invasion of the rete testis) in a clinical trial[8] # 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 - Carboplatin injection is contraindicated in patients with a history of severe allergic reactions to cisplatin or other platinum-containing compounds. - Carboplatin should not be employed in patients with severe bone marrow depression or significant bleeding. # Warnings - Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent and is also the dose-limiting toxicity. Peripheral blood counts should be frequently monitored during carboplatin treatment and, when appropriate, until recovery is achieved. Median nadir occurs at day 21 in patients receiving single-agent carboplatin. In general, single intermittent courses of carboplatin should not be repeated until leukocyte, neutrophil, and platelet counts have recovered. - Since anemia is cumulative, transfusions may be needed during treatment with carboplatin, particularly in patients receiving prolonged therapy. - Bone marrow suppression is increased in patients who have received prior therapy, especially regimens including cisplatin. Marrow suppression is also increased in patients with impaired kidney function. Initial carboplatin dosages in these patients should be appropriately reduced and blood counts should be carefully monitored between courses. The use of carboplatin in combination with other bone marrow suppressing therapies must be carefully managed with respect to dosage and timing in order to minimize additive effects. - Carboplatin has limited nephrotoxic potential, but concomitant treatment with aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution must be exercised when a patient receives both drugs. Clinically significant hearing loss has been reported to occur in pediatric patients when carboplatin was administered at higher than recommended doses in combination with other ototoxic agents. - Carboplatin can induce emesis, which can be more severe in patients previously receiving emetogenic therapy. The incidence and intensity of emesis have been reduced by using premedication with antiemetics. Although no conclusive efficacy data exist with the following schedules of carboplatin, lengthening the duration of single intravenous administration to 24 hours or dividing the total dose over 5 consecutive daily pulse doses has resulted in reduced emesis. - Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 65 years and in patients previously treated with cisplatin. Pre-existing cisplatin-induced neurotoxicity does not worsen in about 70% of the patients receiving carboplatin as secondary treatment. - Loss of vision, which can be complete for light and colors, has been reported after the use of carboplatin with doses higher than those recommended in the package insert. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses. - As in the case of other platinum-coordination compounds, allergic reactions to carboplatin have been reported. These may occur within minutes of administration and should be managed with appropriate supportive therapy. There is increased risk of allergic reactions including anaphylaxis in patients previously exposed to platinum therapy. - High dosages of carboplatin (more than 4 times the recommended dose) have resulted in severe abnormalities of liver function tests. - Carboplatin injection may cause fetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats. There are no adequate and well-controlled studies in pregnant women. 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. Women of childbearing potential should be advised to avoid becoming pregnant. ### Precautions - General - Needles or intravenous administration sets containing aluminum parts that may come in contact with Carboplatin injection should not be used for the preparation or administration of the drug. Aluminum can react with carboplatin causing precipitate formation and loss of potency. # Adverse Reactions ## Clinical Trials Experience - For a comparison of toxicities when carboplatin or cisplatin was given in combination with cyclophosphamide - Use with Cyclophosphamide for Initial Treatment of Ovarian Cancer - Data are based on the experience of 393 patients with ovarian cancer (regardless of baseline status) who received initial combination therapy with carboplatin and cyclophosphamide in two randomized controlled studies conducted by SWOG and NCIC . - Combination with cyclophosphamide as well as duration of treatment may be responsible for the differences that can be noted in the adverse experience table. - Single Agent Use for the Secondary Treatment of Ovarian Cancer - Data are based on the experience of 553 patients with previously treated ovarian carcinoma (regardless of baseline status) who received single-agent carboplatin - In the narrative section that follows, the incidences of adverse events are based on data from 1,893 patients with various types of tumors who received carboplatin as single-agent therapy. - Hematologic Toxicity - Bone marrow suppression is the dose-limiting toxicity of carboplatin. :*Thrombocytopenia with platelet counts below 50,000/mm3 occurs in 25% of the patients (35% of pretreated ovarian cancer patients); neutropenia with granulocyte counts below 1,000/mm3 occurs in 16% of the patients (21% of pretreated ovarian cancer patients); leukopenia with WBC counts below 2,000/mm3 occurs in 15% of the patients (26% of pretreated ovarian cancer patients). The nadir usually occurs about day 21 in patients receiving single-agent therapy. By day 28, 90% of patients have platelet counts above 100,000/mm3; 74% have neutrophil counts above 2,000/mm3; 67% have leukocyte counts above 4,000/mm3. - Marrow suppression is usually more severe in patients with impaired kidney function. Patients with poor performance status have also experienced a higher incidence of severe leukopenia and thrombocytopenia. - The hematologic effects, although usually reversible, have resulted in infectious or hemorrhagic complications in 5% of the patients treated with carboplatin, with drug-related death occurring in less than 1% of the patients. Fever has also been reported in patients with neutropenia. - Anemia with hemoglobin less than 11 g/dL has been observed in 71% of the patients who started therapy with a baseline above that value. The incidence of anemia increases with increasing exposure to carboplatin. Transfusions have been administered to 26% of the patients treated with carboplatin (44% of previously treated ovarian cancer patients). - Bone marrow depression may be more severe when carboplatin is combined with other bone marrow suppressing drugs or with radiotherapy. - Gastrointestinal Toxicity - Vomiting occurs in 65% of the patients (81% of previously treated ovarian cancer patients) and in about one-third of these patients it is severe. Carboplatin, as a single agent or in combination, is significantly less emetogenic than cisplatin; however, patients previously treated with emetogenic agents, especially cisplatin, appear to be more prone to vomiting. Nausea alone occurs in an additional 10 to 15% of patients. Both nausea and vomiting usually cease within 24 hours of treatment and are often responsive to antiemetic measures. Although no conclusive efficacy data exist with the following schedules, prolonged administration of carboplatin, either by continuous 24-hour infusion or by daily pulse doses given for 5 consecutive days, was associated with less severe vomiting than the single-dose intermittent schedule. Emesis was increased when carboplatin was used in combination with other emetogenic compounds. Other gastrointestinal effects observed frequently were pain, in 17% of the patients; diarrhea, in 6%; and constipation, also in 6%. - Neurologic Toxicity - Peripheral neuropathies have been observed in 4% of the patients receiving carboplatin (6% of pretreated ovarian cancer patients) with mild paresthesias occurring most frequently. Carboplatin therapy produces significantly fewer and less severe neurologic side effects than does therapy with cisplatin. However, patients older than 65 years and/or previously treated with cisplatin appear to have an increased risk (10%) for peripheral neuropathies. In 70% of the patients with pre-existing cisplatin-induced peripheral neurotoxicity, there was no worsening of symptoms during therapy with carboplatin. Clinical ototoxicity and other sensory abnormalities such as visual disturbances and change in taste have been reported in only 1% of the patients. Central nervous system symptoms have been reported in 5% of the patients and appear to be most often related to the use of antiemetics. - Although the overall incidence of peripheral neurologic side effects induced by carboplatin is low, prolonged treatment, particularly in cisplatin pretreated patients, may result in cumulative neurotoxicity. - Nephrotoxicity - Development of abnormal renal function test results is uncommon, despite the fact that carboplatin, unlike cisplatin, has usually been administered without high-volume fluid hydration and/or forced diuresis. The incidences of abnormal renal function tests reported are 6% for serum creatinine and 14% for blood urea nitrogen (10% and 22%, respectively, in pretreated ovarian cancer patients). Most of these reported abnormalities have been mild and about one-half of them were reversible. - Creatinine clearance has proven to be the most sensitive measure of kidney function in patients receiving carboplatin, and it appears to be the most useful test for correlating drug clearance and bone marrow suppression. Twenty-seven percent of the patients who had a baseline value of 60 mL/min or more demonstrated a reduction below this value during carboplatin therapy. - Hepatic Toxicity - The incidences of abnormal liver function tests in patients with normal baseline values were reported as follows:total bilirubin, 5%; SGOT, 15%; and alkaline phosphatase, 24%; (5%, 19%, and 37%, respectively, in pretreated ovarian cancer patients). These abnormalities have generally been mild and reversible in about one-half of the cases, although the role of metastatic tumor in the liver may complicate the assessment in many patients. In a limited series of patients receiving very high dosages of carboplatin and autologous bone marrow transplantation, severe abnormalities of liver function tests were reported. - Electrolyte Changes - The incidences of abnormally decreased serum electrolyte values reported were as follows: sodium, 29%; potassium, 20%; calcium, 22%; and magnesium, 29%; (47%, 28%, 31%, and 43%, respectively, in pretreated ovarian cancer patients). Electrolyte supplementation was not routinely administered concomitantly with carboplatin, and these electrolyte abnormalities were rarely associated with symptoms. - Allergic Reactions - Hypersensitivity to carboplatin has been reported in 2% of the patients. These allergic reactions have been similar in nature and severity to those reported with other platinum-containing compounds, i.e, rash, urticaria, erythema,pruritus, and rarely bronchospasm and hypotension. Anaphylactic reactions have been reported as part of postmarketing surveillance . These reactions have been successfully managed with standard epinephrine, corticosteroid, and antihistamine therapy. - Injection Site Reactions - Injection site reactions, including redness, swelling, and pain, have been reported during postmarketing surveillance. Necrosis associated with extravasation has also been reported. - Other Events - Pain and asthenia were the most frequently reported miscellaneous adverse effects; their relationship to the tumor and to anemia was likely. Alopecia was reported (3%). Cardiovascular, respiratory, genitourinary, and mucosal side effects have occurred in 6% or less of the patients. Cardiovascular events (cardiac failure, embolism, cerebrovascular accidents) were fatal in less than 1% of the patients and did not appear to be related to chemotherapy. Cancer-associated hemolytic uremic syndrome has been reported rarely. ## Postmarketing Experience - Malaise, anorexia, hypertension, dehydration, and stomatitis have been reported as part of post marketing surveillance. # Drug Interactions - The renal effects of nephrotoxic compounds may be potentiated by carboplatin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carboplatin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carboplatin during labor and delivery. ### Nursing Mothers Carcinogenesis, Mutagenesis, Impairment of Fertility - The carcinogenic potential of carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established . ### Geriatic Use - Of the 789 patients in initial treatment combination therapy studies (NCIC and SWOG), 395 patients were treated with carboplatin in combination with cyclophosphamide. Of these, 141 were over 65 years of age and 22 were 75 years or older. In these trials, age was not a prognostic factor for survival. In terms of safety, elderly patients treated with carboplatin were more likely to develop severe thrombocytopenia than younger patients. In a combined database of 1,942 patients (414 were ≥65 years of age) that received single-agent carboplatin for different tumor types, a similar incidence of adverse events was seen in patients 65 years and older and in patients less than 65. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because renal function is often decreased in the elderly, renal function should be considered in the selection of carboplatin dosage . ### Gender There is no FDA guidance on the use of Carboplatin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carboplatin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Carboplatin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Carboplatin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carboplatin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carboplatin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring - Peripheral blood counts should be frequently monitored during carboplatin treatment and, when appropriate, until recovery is achieved. # IV Compatibility - Carboplatin injection is a premixed aqueous solution of 10 mg/mL carboplatin. - Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. - When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at room temperature (25° C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin aqueous solutions be discarded 8 hours after dilution. # Overdosage ## Acute Overdose - The anticipated complications of overdosage would be secondary to bone marrow suppression and/or hepatic toxicity. ### Management - There is no known antidote for Carboplatin injection overdosage. # Pharmacology ## Mechanism of Action - Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The aquation of carboplatin, which is thought to produce the active species, occurs at a slower rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions and biological effects. The differences in potencies for carboplatin and cisplatin appear to be directly related to the difference in aquation rates. ## Structure - Carboplatin Injection is for intravenous administration. Each mL contains equivalent to 10 mg of carboplatin in Water for Injection. No other preservatives or additives are present. Carboplatin injection is supplied as a sterile, pyrogen-free, 10 mg/mL aqueous solution of carboplatin. Carboplatin is a platinum coordination compound. The chemical name for carboplatin is platinum, diammine [1,1-cyclobutanedicarboxylato(2-)-O,O’]-,(SP-4-2), and carboplatin has the following structural formula: - Carboplatin is a crystalline powder with the molecular formula of C6H12N2O4Pt and a molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1% solution is 5-7. It is sparingly soluble in water, very slightly soluble in acetone and in alcohol. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Carboplatin in the drug label. ## Pharmacokinetics - In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 300 mg/m2 to 500 mg/m2 of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n=6), and the postdistribution plasma half-life (beta) was found to be 2.6 to 5.9 hours (n=6). The total body clearance, apparent volume of distribution and mean residence time for carboplatin are 4.4 L/hour, 16 L and 3.5 hours, respectively. The Cmax values and areas under the plasma concentration versus time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 mg/m2 to 500 mg/m2). - Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carboplatin are present in plasma. However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days. - The major route of elimination of carboplatin is renal excretion. Patients with creatinine clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour urine is present as carboplatin. Only 3% to 5% of the administered platinum is excreted in the urine between 24 and 96 hours. There are insufficient data to determine whether biliary excretion occurs. - In patients with creatinine clearances below 60 mL/min the total body and renal clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin dosages should therefore be reduced in these patients . - The primary determinant of carboplatin clearance is glomerular filtration rate (GFR) and this parameter of renal function is often decreased in elderly patients. Dosing formulas incorporating estimates of GFR to provide predictable carboplatin plasma AUCs should be used in elderly patients to minimize the risk of toxicity. ## Nonclinical Toxicology - The carcinogenic potential of carboplatin has not been studied, but compounds with similar mechanisms of action and mutagenicity profiles have been reported to be carcinogenic. Carboplatin has been shown to be mutagenic both in vitro and in vivo. It has also been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. Secondary malignancies have been reported in association with multi-drug therapy. # Clinical Studies - In two prospectively randomized, controlled studies conducted by the National Cancer Institute of Canada, Clinical Trials Group (NCIC) and the Southwest Oncology Group (SWOG), 789 chemotherapy naive patients with advanced ovarian cancer were treated with carboplatin or cisplatin, both in combination with cyclophosphamide every 28 days for 6 courses before surgical reevaluation. The following results were obtained from both studies: - The pattern of toxicity exerted by the carboplatin-containing regimen was significantly different from that of the cisplatin-containing combinations. Differences between the two studies may be explained by different cisplatin dosages and by different supportive care. - The carboplatin-containing regimen induced significantly more thrombocytopenia and, in one study, significantly more leukopenia and more need for transfusional support. The cisplatin-containing regimen produced significantly more anemia in one study. However, no significant differences occurred in incidences of infections and hemorrhagic episodes. - Non-hematologic toxicities (emesis, neurotoxicity, ototoxicity, renal toxicity, hypomagnesemia, and alopecia) were significantly more frequent in the cisplatin-containing arms. - In two prospective, randomized controlled studies in patients with advanced ovarian cancer previously treated with chemotherapy, carboplatin achieved 6 clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71 +weeks. # How Supplied - Carboplatin injection - NDC 67457-491-54 50 mg/5 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned. - NDC 67457-492-15 150 mg/15 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned. - NDC 67457-493-46 450 mg/45 mL aqueous solution in multidose vials (with white flip-off seals), individually cartoned. - NDC 67457-494-61 600 mg/60 mL aqueous solution in multidose vials (with blue flip-off seals), individually cartoned. - Storage - Unopened vials of carboplatin injection are stable to the date indicated on the package when stored at 20° - 25° C (68° to 77° F) [see USP Controlled Room Temperature]. Protect from light. - Carboplatin injection multidose vials maintain microbial, chemical, and physical stability for up to 14 days at 25° C following multiple needle entries. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Solutions for infusion should be discarded 8 hours after preparation. - Handling and Disposal - Caution should be exercised in handling and preparing carboplatin injection. Several guidelines on this subject have been published.1-4 - To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing carboplatin injection. If carboplatin injection contacts the skin, immediately wash the skin thoroughly with soap and water. If carboplatin injection contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water. More information is available in the references listed below. ## Storage There is limited information regarding Carboplatin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Carboplatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Paraplatin® - Paraplatin NovaPlus® # Look-Alike Drug Names - CARBOplatin® — CISplatin®[9] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Carboplatin
14688d05a4d102f17d634e9107e771c154e3df44	wikidoc	Carbosulfan	Carbosulfan # Overview Carbosulfan is an organic compound adherent to the carbamate class. At normal conditions, it is brown viscose liquid. It is not very stable; it decomposes slowly at room temperature. Its solubility in water is low but it is miscible with xylene, hexane, chloroform, dichloromethane, methanol and acetone. Carbosulfan is used as an insecticide. The European Union banned use of carbosulfan in 2007. Its oral LD50 for rats is 90 to 250 mg/kg bw, inhalation LC50 is 0.61 mg/L. Carbosulfan is only slightly absorbed through skin (LD50 >2000 mg/kg for rabbits). The mechanism of toxicity is based on reversible inhibition of acetylcholinesterase (as for carbamates generally). Carbosulfan has very low maximum residue limits for use in the EU and UK examples of this can be seen in apples and oranges, where it is 0.05 mg/kg.	Carbosulfan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Carbosulfan is an organic compound adherent to the carbamate class. At normal conditions, it is brown viscose liquid. It is not very stable; it decomposes slowly at room temperature. Its solubility in water is low but it is miscible with xylene, hexane, chloroform, dichloromethane, methanol and acetone. Carbosulfan is used as an insecticide.[1] The European Union banned use of carbosulfan in 2007.[2] Its oral LD50 for rats is 90 to 250 mg/kg bw, inhalation LC50 is 0.61 mg/L. Carbosulfan is only slightly absorbed through skin (LD50 >2000 mg/kg for rabbits). The mechanism of toxicity is based on reversible inhibition of acetylcholinesterase (as for carbamates generally).[3] Carbosulfan has very low maximum residue limits for use in the EU and UK examples of this can be seen in apples and oranges, where it is 0.05 mg/kg.	https://www.wikidoc.org/index.php/Carbosulfan
4dadd052dd2ad4e7a1ba11aba9e7d3ac3c1feaf3	wikidoc	Cardenolide	Cardenolide Cardenolides are a type of steroids. Many plants contain cardenolides in the form of cardenolide glycosides (i.e. cardenolides that contain structural groups derived from sugars; see Glycoside). Cardenolides are toxic (specifically, heart-arresting). # Etymology Supposedly, the term derives from Greek kardiā, heart. It shouldn't be confused with cardanolides. Cardanolides are a class of steroids (or aglycones if viewed as cardiac glycoside constituents), and cardenolides are a subtype of this class (see MeSH D codes list). # Structure Cardenolides are C(23)-steroids with methyl groups at C-10 and C-13 and a five-membered lactone at C-17. They are aglycone constituents of cardiac glycosides and must have at least one double bond in the molecule. The class includes cardadienolides and cardatrienolides. Members include: - digitoxin - acetyldigitoxins - digitoxigenin - digoxin - acetyldigoxins - digoxigenin - medigoxin - strophanthins - cymarine - ouabain - strophanthidin # As defense mechanism Some plant and animal species use cardenolides as a defense mechanism, most notably the monarch butterflies. Adult monarch butterflies store the cardenolides they have built-up as larvae feeding mostly on milkweeds (Asclepias). The cardenolide content in butterflies deters vertebrate predators, with some exceptions of cardenolide-tolerant predators like black-backed orioles (Icterus abeillei Lesson) and black headed grosbeaks (Pheucticus melanocephalus Swainson) that account for 60% of monarch butterfly mortalities in the overwintering sites in central Mexico.	Cardenolide Cardenolides are a type of steroids. Many plants contain cardenolides in the form of cardenolide glycosides (i.e. cardenolides that contain structural groups derived from sugars; see Glycoside). Cardenolides are toxic (specifically, heart-arresting). # Etymology Supposedly, the term derives from Greek kardiā, heart. It shouldn't be confused with cardanolides. Cardanolides are a class of steroids (or aglycones if viewed as cardiac glycoside constituents), and cardenolides are a subtype of this class (see MeSH D codes list). # Structure Cardenolides are C(23)-steroids with methyl groups at C-10 and C-13 and a five-membered lactone at C-17. They are aglycone constituents of cardiac glycosides and must have at least one double bond in the molecule. The class includes cardadienolides and cardatrienolides. Members include: - digitoxin - acetyldigitoxins - digitoxigenin - digoxin - acetyldigoxins - digoxigenin - medigoxin - strophanthins - cymarine - ouabain - strophanthidin # As defense mechanism Some plant and animal species use cardenolides as a defense mechanism, most notably the monarch butterflies. Adult monarch butterflies store the cardenolides they have built-up as larvae feeding mostly on milkweeds (Asclepias). The cardenolide content in butterflies deters vertebrate predators, with some exceptions of cardenolide-tolerant predators like black-backed orioles (Icterus abeillei Lesson) and black headed grosbeaks (Pheucticus melanocephalus Swainson) that account for 60% of monarch butterfly mortalities in the overwintering sites in central Mexico.	https://www.wikidoc.org/index.php/Cardenolide
970f9442580d8a41bfd38e3d0274e3e5773ee508	wikidoc	Cardiolipin	Cardiolipin # Overview Cardiolipin (bisphosphatidyl glycerol) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid. # Function and structure It is typically present in metabolically active cells of the heart and skeletal muscle, in the membranes of their mitochondria, mostly in the inner membrane, and consists roughly 20% of its lipids . It has also been observed in certain bacterial membranes. It serves as an insulator and stabilizes the activity of protein complexes important to the electron transport chain. It also "glues" them together. Cardiolipin is a "double" phospholipid because it has four fatty acid tails, instead of the usual two. # Clinical significance ## Barth syndrome Barth syndrome is a rare genetic disorder that was recognised in the 1970's to cause infantile death. It has a mutation in the gene coding for tafazzin, an enzyme involved in the biosynthesis of cardiolipin. Girls heterozygous for the trait are unaffected. Sufferers of this condition have mitochondria that are abnormal, and they cannot sustain adequate production of ATP. Cardiomyopathy and general weakness is common to these patients. Cardiolipin treats the symptoms of BTHS and prevents infections. ## Diabetes Heart disease hits people with diabetes twice as often as people without diabetes. In those with diabetes, cardiovascular complications occur at an earlier age and often result in premature death, making heart disease the major killer of diabetic people. Cardiolipin has recently been found to be deficient in the heart at the earliest stages of diabetes, possibly due to a lipid-digesting enzyme that becomes more active in diabetic heart muscle. ## Antiphospholipid syndrome Patients with anti-cardiolipin antibodies (Antiphospholipid syndrome) can have recurrent thrombotic events even early in their mid-late teen years. These events can occur in vessels where thrombosis may be relatively uncommon, such as the hepatic or renal veins. These antibodies are usually picked up in young women with recurrent spontaneous abortions. In anti-cardiolipin mediated autoimmune disease there is a dependency on the apolipoprotein H for recognition. ## Syphilis Cardiolipin from a cow heart is used as an antigen in the Wassermann test for syphilis. Anti-cardiolipin antibodies can also be increased in numerous other conditions, including malaria and tuberculosis, so this test is not specific.	Cardiolipin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Cardiolipin (bisphosphatidyl glycerol) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid. # Function and structure It is typically present in metabolically active cells of the heart and skeletal muscle, in the membranes of their mitochondria, mostly in the inner membrane, and consists roughly 20% of its lipids [1]. It has also been observed in certain bacterial membranes. It serves as an insulator and stabilizes the activity of protein complexes important to the electron transport chain. It also "glues" them together[2]. Cardiolipin is a "double" phospholipid because it has four fatty acid tails, instead of the usual two. # Clinical significance ## Barth syndrome Barth syndrome is a rare genetic disorder that was recognised in the 1970's to cause infantile death. It has a mutation in the gene coding for tafazzin, an enzyme involved in the biosynthesis of cardiolipin. Girls heterozygous for the trait are unaffected. Sufferers of this condition have mitochondria that are abnormal, and they cannot sustain adequate production of ATP. Cardiomyopathy and general weakness is common to these patients. Cardiolipin treats the symptoms of BTHS and prevents infections. ## Diabetes Heart disease hits people with diabetes twice as often as people without diabetes. In those with diabetes, cardiovascular complications occur at an earlier age and often result in premature death, making heart disease the major killer of diabetic people. Cardiolipin has recently been found to be deficient in the heart at the earliest stages of diabetes, possibly due to a lipid-digesting enzyme that becomes more active in diabetic heart muscle.[2] ## Antiphospholipid syndrome Patients with anti-cardiolipin antibodies (Antiphospholipid syndrome) can have recurrent thrombotic events even early in their mid-late teen years. These events can occur in vessels where thrombosis may be relatively uncommon, such as the hepatic or renal veins. These antibodies are usually picked up in young women with recurrent spontaneous abortions. In anti-cardiolipin mediated autoimmune disease there is a dependency on the apolipoprotein H for recognition.[3] ## Syphilis Cardiolipin from a cow heart is used as an antigen in the Wassermann test for syphilis. Anti-cardiolipin antibodies can also be increased in numerous other conditions, including malaria and tuberculosis, so this test is not specific.	https://www.wikidoc.org/index.php/Cardiolipin
cebb340cac054be111c5db6ecfdd470aaa53dfa8	wikidoc	Carfentanil	Carfentanil Carfentanil or Carfentanyl (R33799) is an analogue of the popular synthetic opioid analgesic fentanyl, and is one of the most potent opioids known (also the most potent opioid used commercially). Carfentanil was discovered by Janssen Pharmaceutica. It has a quantitative potency approximately 10,000 times that of morphine and 100 times that of fentanyl, activity in humans starting at about 1 μg. It is marketed under the trade name Wildnil as a tranquilizer for large animals. Carfentanil is intended for animal use only as its extreme potency makes it inappropriate for use in humans. A good practical example of the drug in use in veterinary practice was shown in an episode of the Discovery Channel series, Animal Cops: Houston, where carfentanil was administered orally (dissolved in honey, specifically) to a full-grown brown bear to tranquilize it so that it could be safely relocated to the Houston Zoo from a south Texas animal abuser's property. A few tablespoons' worth of the anesthetic was sufficient to put the grizzly bear, weighing more than 1000 pounds, to sleep. # Moscow theater hostage crisis It is thought that in the 2002 Moscow theater hostage crisis, the Russian military made use of an aerosol form of either carfentanil or another similar drug such as 3-methylfentanyl to subdue Chechen hostage takers. Its short action, easy reversibility and therapeutic index (10600 vs. 300 for fentanyl) would make it a near-perfect agent for this purpose. Wax et al. surmise from the available evidence that the Moscow emergency services had not been informed of the use of the agent, and therefore did not have adequate supplies of naloxone or naltrexone (opioid antagonists) to prevent complications in many of the victims. Assuming that carfentanil was the only active constituent (which has not been verified by the Russian military), the primary acute toxic effect to the theatre victims would have been opioid-induced apnea; in this case mechanical ventilation and/or treatment with opioid antagonists would have been life-saving for many or all victims.	Carfentanil Carfentanil or Carfentanyl (R33799) is an analogue of the popular synthetic opioid analgesic fentanyl, and is one of the most potent opioids known (also the most potent opioid used commercially). Carfentanil was discovered by Janssen Pharmaceutica. It has a quantitative potency approximately 10,000 times that of morphine and 100 times that of fentanyl, activity in humans starting at about 1 μg. It is marketed under the trade name Wildnil as a tranquilizer for large animals.[1] Carfentanil is intended for animal use only as its extreme potency makes it inappropriate for use in humans. A good practical example of the drug in use in veterinary practice was shown in an episode of the Discovery Channel series, Animal Cops: Houston, where carfentanil was administered orally (dissolved in honey, specifically) to a full-grown brown bear to tranquilize it so that it could be safely relocated to the Houston Zoo from a south Texas animal abuser's property. A few tablespoons' worth of the anesthetic was sufficient to put the grizzly bear, weighing more than 1000 pounds, to sleep. # Moscow theater hostage crisis It is thought that in the 2002 Moscow theater hostage crisis, the Russian military made use of an aerosol form of either carfentanil or another similar drug such as 3-methylfentanyl to subdue Chechen hostage takers.[2] Its short action, easy reversibility and therapeutic index (10600 vs. 300 for fentanyl) would make it a near-perfect agent for this purpose. Wax et al. surmise from the available evidence that the Moscow emergency services had not been informed of the use of the agent, and therefore did not have adequate supplies of naloxone or naltrexone (opioid antagonists) to prevent complications in many of the victims. Assuming that carfentanil was the only active constituent (which has not been verified by the Russian military), the primary acute toxic effect to the theatre victims would have been opioid-induced apnea; in this case mechanical ventilation and/or treatment with opioid antagonists would have been life-saving for many or all victims.	https://www.wikidoc.org/index.php/Carfentanil
8aaf8f3d1d5e9fa330284d2ae81d9f2c9d1fa39e	wikidoc	Carfilzomib	Carfilzomib # 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 Carfilzomib is a proteasome inhibitor that is FDA approved for the treatment of multiple myeloma. Common adverse reactions include fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Carfilzomib is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. - Dosing Guidelines - Carfilzomib is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle (Table 1). - In Cycle 1, Carfilzomib is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs. - The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface are of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%. - Hydration and Fluid Monitoring - Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with Carfilzomib treatment. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following Carfilzomib administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload. - Dexamethasone Premedication - Pre-medicate with dexamethasone 4 mg orally or intravenously prior to all doses of Carfilzomib during Cycle 1 and prior to all Carfilzomib doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. - Dose Modifications Based on Toxicities - Recommended actions and dose modifications are presented in Table 2. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carfilzomib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carfilzomib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Carfilzomib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carfilzomib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carfilzomib in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia - Death due to cardiac arrest has occurred within a day of Carfilzomib administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of Carfilzomib. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold Carfilzomib for Grade 3 or 4 cardiac events until recovery and consider whether to restart Carfilzomib based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. - Pulmonary Hypertension - Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with Carfilzomib and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Carfilzomib for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Carfilzomib based on a benefit/risk assessment. - Pulmonary Complications - Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt Carfilzomib until symptoms have resolved or returned to baseline. - Infusion Reactions - Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Carfilzomib. Administer dexamethasone prior to Carfilzomib to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur. - Tumor Lysis Syndrome - Tumor lysis syndrome (TLS) occurred following Carfilzomib administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving Carfilzomib, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt Carfilzomib until TLS is resolved. - Thrombocytopenia - Carfilzomib causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following Carfilzomib administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with Carfilzomib in < 1% of patients. Monitor platelet counts frequently during treatment with Carfilzomib. Reduce or interrupt dose as clinically indicated. - Hepatic Toxicity and Hepatic Failure - Cases of hepatic failure, including fatal cases, have been reported (< 1%). Carfilzomib can cause elevations of serum transaminases and bilirubin. Withhold Carfilzomib in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting Carfilzomib is appropriate. Monitor liver enzymes frequently. - Embryo-fetal Toxicity - Carfilzomib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using Carfilzomib. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. - Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Carfilzomib. 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. # 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 with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice. - A total of 526 patients with relapsed and/or refractory multiple myeloma received Carfilzomib as monotherapy or with pre-dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative Carfilzomib dose of 993.4 mg. - Deaths due to all causes within 30 days of the last dose of Carfilzomib occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end-organ failure in 4 patients (multi-organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes. - Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of Carfilzomib occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). - Adverse reactions occurring at a rate of 10% or greater are presented in Table 4. - Renal Events - The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function. - Peripheral Neuropathy - Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended. - Herpes Virus Infection - Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Carfilzomib in the drug label. # Drug Interactions - Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Carfilzomib. Based on its mechanism of action and findings in animals, Carfilzomib can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If Carfilzomib 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. - Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carfilzomib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carfilzomib during labor and delivery. ### Nursing Mothers - It is not known whether Carfilzomib is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Carfilzomib, 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 effectiveness of Carfilzomib in pediatric patients have not been established. ### Geriatic Use - In studies of Carfilzomib there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older. ### Gender There is no FDA guidance on the use of Carfilzomib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carfilzomib with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics and safety of Carfilzomib were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using Carfilzomib doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond. The pharmacokinetics and safety of Carfilzomib were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of Carfilzomib concentrations has not been studied, the drug should be administered after the dialysis procedure. ### Hepatic Impairment - The safety, efficacy and pharmacokinetics of Carfilzomib have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the Carfilzomib clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carfilzomib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carfilzomib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Carfilzomib in the drug label. # IV Compatibility # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Carfilzomib in the drug label. # Pharmacology ## Mechanism of Action - Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors. ## Structure - Carfilzomib (carfilzomib) for Injection is an antineoplastic agent available for intravenous use only. Carfilzomib is a sterile, white to off-white lyophilized powder and is available as a single-use vial. Each vial of Carfilzomib contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5). - Carfilzomib is a modified tetrapeptidyl epoxide, isolated as the crystalline free base. The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. Carfilzomib has the following structure: - Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular formula is C40H57N5O7. Carfilzomib is practically insoluble in water, and very slightly soluble in acidic conditions. ## Pharmacodynamics - Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like activity when measured in blood 1 hour after the first dose. On Day 1 of Cycle 1, proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 mg/m2, and from 82% to 83% at 20 mg/m2. In addition, carfilzomib administration resulted in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing. ## Pharmacokinetics - Absorption: The Cmax and AUC following a single intravenous dose of 27 mg/m2 was 4232 ng/mL and 379 nghr/mL, respectively. Following repeated doses of carfilzomib at 15 and 20 mg/m2, systemic exposure (AUC) and half-life were similar on Days 1 and 15 or 16 of Cycle 1, suggesting there was no systemic carfilzomib accumulation. At doses between 20 and 36 mg/m2, there was a dose-dependent increase in exposure. - Distribution: The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib was 28 L. When tested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over the concentration range of 0.4 to 4 micromolar. - Metabolism: Carfilzomib was rapidly and extensively metabolized. The predominant metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450-mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity. - Elimination: Following intravenous administration of doses ≥ 15 mg/m2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely cleared extrahepatically. The pathways of carfilzomib elimination have not been characterized in humans. - Age: Analysis of population pharmacokinetics data after the first dose of Cycle 1 (Day 1) in 154 patients who had received an IV dose of 20 mg/m2 showed no clinically significant difference in exposure between patients < 65 years and ≥ 65 years of age. - Gender: Mean dose-normalized AUC and Cmax values were comparable between male and female patients in the population pharmacokinetics study. - Hepatic Impairment: No pharmacokinetic studies were performed with Carfilzomib in patients with hepatic impairment. - Renal Impairment: A pharmacokinetic study was conducted in which 43 multiple myeloma patients who had various degrees of renal impairment and who were classified according to their creatinine clearances (CLcr) into the following groups: normal function (CLcr > 80 mL/min, n = 8), mild impairment (CLcr 50–80 mL/min, n = 12), moderate impairment (CLcr 30–49 mL/min, n = 8), severe impairment (CLcr < 30 mL/min, n = 7), and chronic dialysis (n = 8). Carfilzomib was administered intravenously over 2 to 10 minutes, on two consecutive days, weekly for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period every 28 days. Patients received an initial dose of 15 mg/m2, which could be escalated to 20 mg/m2 starting in Cycle 2 if 15 mg/m2 was well tolerated in Cycle 1. In this study, renal function status had no effect on the clearance or exposure of carfilzomib following a single or repeat-dose administration. - Cytochrome P450: In an in vitro study using human liver microsomes, carfilzomib showed modest direct and time-dependent inhibitory effect on human cytochrome CYP3A4/5. In vitro studies indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism of carfilzomib. A clinical trial of 17 patients using oral midazolam as a CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration. Carfilzomib is not expected to inhibit CYP3A4/5 activities and/or affect the exposure to CYP3A4/5 substrates. - P-gp: Carfilzomib is a P-glycoprotein (P-gp) substrate and showed marginal inhibitory effects on P-gp in a Caco-2 monolayer system. Given that Carfilzomib is administrated intravenously and is extensively metabolized, the pharmacokinetic profile of Carfilzomib is unlikely to be affected by P-gp inhibitors or inducers. ## Nonclinical Toxicology - Carcinogenicity studies have not been conducted with carfilzomib. - Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. - Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies. # Clinical Studies - The safety and efficacy of Carfilzomib were evaluated in a single-arm, multicenter clinical trial. Two hundred and sixty-six patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) were enrolled. Patients were enrolled in the trial whose disease had a less than or equal to 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial with total bilirubin levels ≥ 2 × upper limit of normal (ULN); creatinine clearance rates < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; and pleural effusion. - Carfilzomib was administered intravenously over 2 to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m2 at each dose in Cycle 1, and 27 mg/m2 in subsequent cycles. To reduce the incidence and severity of fever, rigors, chills, dyspnea, myalgia, and arthralgia, dexamethasone 4 mg by mouth or by intravenous infusion was administered prior to all Carfilzomib doses during the first cycle and prior to all Carfilzomib doses during the first dose-escalation (27 mg/m2) cycle. Dexamethasone premedication (4 mg orally or intravenously) was reinstated if these symptoms reappeared during subsequent cycles. - Baseline patient and disease characteristics are summarized in Table 5. - The median number of cycles started was four. - The primary endpoint was the overall response rate (ORR) as determined by Independent Review Committee assessment using International Myeloma Working Group criteria. The ORR (stringent complete response + complete response + very good partial response + partial response ) was 22.9% (95% CI: 18.0, 28.5) (N = 266) (see Table 6). The median duration of response (DOR) was 7.8 months (95% CI: 5.6, 9.2). # How Supplied - Carfilzomib (carfilzomib) for Injection is supplied as an individually cartoned single-use vial containing a dose of 60 mg of carfilzomib as a white to off-white lyophilized cake or powder. - NDC 76075-101-01, 60 mg carfilzomib per vial - Storage and Handling - Unopened vials should be stored refrigerated (2°C to 8°C; 36°F to 46°F). Retain in original package to protect from light. ## Storage There is limited information regarding Carfilzomib Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Discuss the following with patients prior to treatment with Carfilzomib: - Instruct patients to contact their physician if they develop any of the following symptoms: fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. - Advise patients that Carfilzomib may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms. - Advise patients that they may experience shortness of breath (dyspnea) during treatment with Carfilzomib. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath. - Counsel patients to avoid dehydration, since patients receiving Carfilzomib therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells. - Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with Carfilzomib. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take Carfilzomib treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discus # Precautions with Alcohol - Alcohol-Carfilzomib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - KYPROLIS® # Look-Alike Drug Names There is limited information regarding Carfilzomib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Carfilzomib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [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 Carfilzomib is a proteasome inhibitor that is FDA approved for the treatment of multiple myeloma. Common adverse reactions include fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Carfilzomib is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. - Dosing Guidelines - Carfilzomib is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle (Table 1). - In Cycle 1, Carfilzomib is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs. - The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface are of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%. - Hydration and Fluid Monitoring - Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with Carfilzomib treatment. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250 mL to 500 mL of intravenous fluids as needed following Carfilzomib administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload. - Dexamethasone Premedication - Pre-medicate with dexamethasone 4 mg orally or intravenously prior to all doses of Carfilzomib during Cycle 1 and prior to all Carfilzomib doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. - Dose Modifications Based on Toxicities - Recommended actions and dose modifications are presented in Table 2. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carfilzomib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carfilzomib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Carfilzomib in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Carfilzomib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Carfilzomib in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia - Death due to cardiac arrest has occurred within a day of Carfilzomib administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of Carfilzomib. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold Carfilzomib for Grade 3 or 4 cardiac events until recovery and consider whether to restart Carfilzomib based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. - Pulmonary Hypertension - Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with Carfilzomib and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Carfilzomib for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Carfilzomib based on a benefit/risk assessment. - Pulmonary Complications - Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt Carfilzomib until symptoms have resolved or returned to baseline. - Infusion Reactions - Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Carfilzomib. Administer dexamethasone prior to Carfilzomib to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur. - Tumor Lysis Syndrome - Tumor lysis syndrome (TLS) occurred following Carfilzomib administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving Carfilzomib, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt Carfilzomib until TLS is resolved. - Thrombocytopenia - Carfilzomib causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following Carfilzomib administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with Carfilzomib in < 1% of patients. Monitor platelet counts frequently during treatment with Carfilzomib. Reduce or interrupt dose as clinically indicated. - Hepatic Toxicity and Hepatic Failure - Cases of hepatic failure, including fatal cases, have been reported (< 1%). Carfilzomib can cause elevations of serum transaminases and bilirubin. Withhold Carfilzomib in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting Carfilzomib is appropriate. Monitor liver enzymes frequently. - Embryo-fetal Toxicity - Carfilzomib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using Carfilzomib. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. - Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Carfilzomib. 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. # 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 with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice. - A total of 526 patients with relapsed and/or refractory multiple myeloma received Carfilzomib as monotherapy or with pre-dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative Carfilzomib dose of 993.4 mg. - Deaths due to all causes within 30 days of the last dose of Carfilzomib occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end-organ failure in 4 patients (multi-organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes. - Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of Carfilzomib occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). - Adverse reactions occurring at a rate of 10% or greater are presented in Table 4. - Renal Events - The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function. - Peripheral Neuropathy - Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended. - Herpes Virus Infection - Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Carfilzomib in the drug label. # Drug Interactions - Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Carfilzomib. Based on its mechanism of action and findings in animals, Carfilzomib can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If Carfilzomib 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. - Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carfilzomib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Carfilzomib during labor and delivery. ### Nursing Mothers - It is not known whether Carfilzomib is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Carfilzomib, 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 effectiveness of Carfilzomib in pediatric patients have not been established. ### Geriatic Use - In studies of Carfilzomib there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older. ### Gender There is no FDA guidance on the use of Carfilzomib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Carfilzomib with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics and safety of Carfilzomib were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using Carfilzomib doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond. The pharmacokinetics and safety of Carfilzomib were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of Carfilzomib concentrations has not been studied, the drug should be administered after the dialysis procedure. ### Hepatic Impairment - The safety, efficacy and pharmacokinetics of Carfilzomib have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the Carfilzomib clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Carfilzomib in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Carfilzomib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Carfilzomib in the drug label. # IV Compatibility # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Carfilzomib in the drug label. # Pharmacology ## Mechanism of Action - Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors. ## Structure - Carfilzomib (carfilzomib) for Injection is an antineoplastic agent available for intravenous use only. Carfilzomib is a sterile, white to off-white lyophilized powder and is available as a single-use vial. Each vial of Carfilzomib contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5). - Carfilzomib is a modified tetrapeptidyl epoxide, isolated as the crystalline free base. The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. Carfilzomib has the following structure: - Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular formula is C40H57N5O7. Carfilzomib is practically insoluble in water, and very slightly soluble in acidic conditions. ## Pharmacodynamics - Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like activity when measured in blood 1 hour after the first dose. On Day 1 of Cycle 1, proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 mg/m2, and from 82% to 83% at 20 mg/m2. In addition, carfilzomib administration resulted in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing. ## Pharmacokinetics - Absorption: The Cmax and AUC following a single intravenous dose of 27 mg/m2 was 4232 ng/mL and 379 ng•hr/mL, respectively. Following repeated doses of carfilzomib at 15 and 20 mg/m2, systemic exposure (AUC) and half-life were similar on Days 1 and 15 or 16 of Cycle 1, suggesting there was no systemic carfilzomib accumulation. At doses between 20 and 36 mg/m2, there was a dose-dependent increase in exposure. - Distribution: The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib was 28 L. When tested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over the concentration range of 0.4 to 4 micromolar. - Metabolism: Carfilzomib was rapidly and extensively metabolized. The predominant metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450-mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity. - Elimination: Following intravenous administration of doses ≥ 15 mg/m2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely cleared extrahepatically. The pathways of carfilzomib elimination have not been characterized in humans. - Age: Analysis of population pharmacokinetics data after the first dose of Cycle 1 (Day 1) in 154 patients who had received an IV dose of 20 mg/m2 showed no clinically significant difference in exposure between patients < 65 years and ≥ 65 years of age. - Gender: Mean dose-normalized AUC and Cmax values were comparable between male and female patients in the population pharmacokinetics study. - Hepatic Impairment: No pharmacokinetic studies were performed with Carfilzomib in patients with hepatic impairment. - Renal Impairment: A pharmacokinetic study was conducted in which 43 multiple myeloma patients who had various degrees of renal impairment and who were classified according to their creatinine clearances (CLcr) into the following groups: normal function (CLcr > 80 mL/min, n = 8), mild impairment (CLcr 50–80 mL/min, n = 12), moderate impairment (CLcr 30–49 mL/min, n = 8), severe impairment (CLcr < 30 mL/min, n = 7), and chronic dialysis (n = 8). Carfilzomib was administered intravenously over 2 to 10 minutes, on two consecutive days, weekly for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period every 28 days. Patients received an initial dose of 15 mg/m2, which could be escalated to 20 mg/m2 starting in Cycle 2 if 15 mg/m2 was well tolerated in Cycle 1. In this study, renal function status had no effect on the clearance or exposure of carfilzomib following a single or repeat-dose administration. - Cytochrome P450: In an in vitro study using human liver microsomes, carfilzomib showed modest direct and time-dependent inhibitory effect on human cytochrome CYP3A4/5. In vitro studies indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism of carfilzomib. A clinical trial of 17 patients using oral midazolam as a CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration. Carfilzomib is not expected to inhibit CYP3A4/5 activities and/or affect the exposure to CYP3A4/5 substrates. - P-gp: Carfilzomib is a P-glycoprotein (P-gp) substrate and showed marginal inhibitory effects on P-gp in a Caco-2 monolayer system. Given that Carfilzomib is administrated intravenously and is extensively metabolized, the pharmacokinetic profile of Carfilzomib is unlikely to be affected by P-gp inhibitors or inducers. ## Nonclinical Toxicology - Carcinogenicity studies have not been conducted with carfilzomib. - Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. - Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies. # Clinical Studies - The safety and efficacy of Carfilzomib were evaluated in a single-arm, multicenter clinical trial. Two hundred and sixty-six patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) were enrolled. Patients were enrolled in the trial whose disease had a less than or equal to 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial with total bilirubin levels ≥ 2 × upper limit of normal (ULN); creatinine clearance rates < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; and pleural effusion. - Carfilzomib was administered intravenously over 2 to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m2 at each dose in Cycle 1, and 27 mg/m2 in subsequent cycles. To reduce the incidence and severity of fever, rigors, chills, dyspnea, myalgia, and arthralgia, dexamethasone 4 mg by mouth or by intravenous infusion was administered prior to all Carfilzomib doses during the first cycle and prior to all Carfilzomib doses during the first dose-escalation (27 mg/m2) cycle. Dexamethasone premedication (4 mg orally or intravenously) was reinstated if these symptoms reappeared during subsequent cycles. - Baseline patient and disease characteristics are summarized in Table 5. - The median number of cycles started was four. - The primary endpoint was the overall response rate (ORR) as determined by Independent Review Committee assessment using International Myeloma Working Group criteria. The ORR (stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]) was 22.9% (95% CI: 18.0, 28.5) (N = 266) (see Table 6). The median duration of response (DOR) was 7.8 months (95% CI: 5.6, 9.2). # How Supplied - Carfilzomib (carfilzomib) for Injection is supplied as an individually cartoned single-use vial containing a dose of 60 mg of carfilzomib as a white to off-white lyophilized cake or powder. - NDC 76075-101-01, 60 mg carfilzomib per vial - Storage and Handling - Unopened vials should be stored refrigerated (2°C to 8°C; 36°F to 46°F). Retain in original package to protect from light. ## Storage There is limited information regarding Carfilzomib Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Discuss the following with patients prior to treatment with Carfilzomib: - Instruct patients to contact their physician if they develop any of the following symptoms: fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. - Advise patients that Carfilzomib may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms. - Advise patients that they may experience shortness of breath (dyspnea) during treatment with Carfilzomib. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath. - Counsel patients to avoid dehydration, since patients receiving Carfilzomib therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells. - Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with Carfilzomib. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take Carfilzomib treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discus # Precautions with Alcohol - Alcohol-Carfilzomib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - KYPROLIS®[1] # Look-Alike Drug Names There is limited information regarding Carfilzomib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Carfilzomib
f9c5b91ca9948b50cb285161931c4e3c602a42ae	wikidoc	Cariprazine	Cariprazine # 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 Cariprazine is an atypical antipsychotic that is FDA approved for the treatment of patients with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include extrapyramidal symptoms and akathisia in Schizophrenia patients and extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness in patients with Bipolar mania (≥5%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cariprazine is indicated for the: - Treatment of schizophrenia - Acute treatment of manic or mixed episodes associated with bipolar I disorder Cariprazine is given orally once daily and can be taken with or without food. Because of the long half-life of Cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Prescribers should monitor patients for adverse reactions and treatment response for several weeks after starting Cariprazine and after each dosage change. The maximum recommended dose is 6 mg daily. In short-term controlled trials, dosages above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. - Schizophrenia The recommended dose range is 1.5 mg to 6 mg once daily. The starting dose of Cariprazine is 1.5 mg. The dosage can be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. - Manic or Mixed Episodes Associated with Bipolar I Disorder The recommended dose range is 3 mg to 6 mg once daily. The starting dose of Cariprazine is 1.5 mg and should be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. - Dosage Adjustments for CYP3A4 Inhibitors and Inducers CYP3A4 is responsible for the formation and elimination of the major active metabolites of Cariprazine. - Dosage recommendation for patients initiating a strong CYP3A4 inhibitor while on a stable dose of Cariprazine: If a strong CYP3A4 inhibitor is initiated, reduce the current dosage of Cariprazine by half. For patients taking 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking 1.5 mg daily, the dosing regimen should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, Cariprazine dosage may need to be increased. - Dosage recommendation for patients initiating Cariprazine therapy while already on a strong CYP3A4 inhibitor: Patients should be administered 1.5 mg of Cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, Cariprazine dosage may need to be increased. - Dosage recommendation for patients concomitantly taking Cariprazine with CYP3A4 inducers:Concomitant use of Cariprazine and a CYP3A4 inducer has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear. - Treatment Discontinuation Following discontinuation of Cariprazine, the decline in plasma concentrations of active drug and metabolites may not be immediately reflected in patients' clinical symptoms; the plasma concentration of Cariprazine and its active metabolites will decline by 50% in ~1 week. There are no systematically collected data to specifically address switching patients from Cariprazine to other antipsychotics or concerning concomitant administration with other antipsychotics. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cariprazine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cariprazine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. Pediatric studies of Cariprazine have not been conducted. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cariprazine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cariprazine in pediatric patients. # Contraindications Cariprazine is contraindicated in patients with history of a hypersensitivity reaction to Cariprazine. Reactions have ranged from rash, pruritus, urticaria, and events suggestive of angioedema (e.g., swollen tongue, lip swelling, face edema, pharyngeal edema, and swelling face). # Warnings Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue Cariprazine and provide intensive symptomatic treatment and monitoring. Cariprazine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including Cariprazine. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. There is no known treatment for tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Given these considerations, Cariprazine should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on Cariprazine, drug discontinuation should be considered. However, some patients may require treatment with Cariprazine despite the presence of the syndrome. Adverse events may first appear several weeks after the initiation of Cariprazine treatment, probably because plasma levels of Cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures. Monitor for adverse reactions, including EPS or akathisia, and patient response for several weeks after a patient has begun Cariprazine and after each dosage increase. Consider reducing the dose or discontinuing the drug. Atypical antipsychotic drugs, including Cariprazine, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile. - Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment. - Schizophrenia In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with Cariprazine and placebo. In the long-term, open-label schizophrenia studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels ( ≥6.5%). - Bipolar Mania In the 3-week, placebo-controlled trials of adult patients with bipolar disorder, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with Cariprazine and placebo. In the long-term, open-label bipolar disorder studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥6.5%). - Dyslipidemia Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. - Schizophrenia In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with Cariprazine and placebo. - Bipolar Mania In the 3-week, placebo-controlled trials of adult patients with bipolar disorder, the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with Cariprazine and placebo. - Weight Gain Weight gain has been observed with use of atypical antipsychotics, including Cariprazine. Monitor weight at baseline and frequently thereafter. TABLES 1 and 2 show the change in body weight occurring from baseline to endpoint in 6-week schizophrenia and 3-week bipolar mania trials. - Table 1. Change in Body Weight (kg) in 6-Week Schizophrenia Trials VRAYLAR: Cariprazine's Brand name - Table 2. Change in Body Weight (kg) in 3-Week Bipolar Mania Trials VRAYLAR: Cariprazine's Brand name In long-term, uncontrolled trials with Cariprazine in schizophrenia, the mean changes from baseline in weight at 12, 24, and 48 weeks were 1.2 kg, 1.7 kg, and 2.5 kg, respectively. Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including Cariprazine. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Cariprazine at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue Cariprazine in patients with absolute neutrophil count < 1000/mm3 and follow their WBC until recovery. Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Symptomatic orthostatic hypotension was infrequent in trials of Cariprazine and was not more frequent on Cariprazine than placebo. Syncope was not observed. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. Cariprazine has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials. Like other antipsychotic drugs, Cariprazine may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients. Cariprazine, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In 6-week schizophrenia trials, somnolence (hypersomnia, sedation, and somnolence) was reported in 7% of Cariprazine-treated patients compared to 6% of placebo-treated patients. In 3-week bipolar mania trials, somnolence was reported in 8% of Cariprazine-treated patients compared to 4% of placebo-treated patients. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with Cariprazine does not affect them adversely. Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use Cariprazine with caution in patient who may experience these conditions. Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with Cariprazine. Cariprazine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are discussed in more detail in other sections of the labeling: - Increased Mortality in Elderly Patients with Dementia-Related Psychosis - Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis - Neuroleptic Malignant Syndrome - Tardive Dyskinesia - Late Occurring Adverse Reactions - Metabolic Changes - Leukopenia, Neutropenia, and Agranulocytosis - Orthostatic Hypotension and Syncope - Seizures - Potential for Cognitive and Motor Impairment - Body Temperature Dysregulation - Dysphagia 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 information below is derived from the clinical trial database for Cariprazine, consisting of 1733 patients with schizophrenia (aged 18 to 65) and 1025 patients with manic or mixed episodes associated with bipolar I disorder (aged 18 to 65) exposed to one or more doses with a total experience of 566.5 patient-years. Of these patients, 1317 participated in placebo-controlled, 6-week schizophrenia trials with doses ranging from 1.5 mg to 12 mg/day and 623 participated in placebo-controlled, 3-week bipolar mania trials with doses ranging from 3 mg to 12 mg/day. A total of 364 Cariprazine-treated patients had at least 24 weeks of exposure and 239 Cariprazine-treated patients had at least 48 weeks of exposure. Patients with Schizophrenia The following findings are based on four placebo-controlled, 6-week schizophrenia trials with Cariprazine doses ranging from 1.5 to 12 mg once daily. - Adverse Reactions Associated with Discontinuation of Treatment: There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in Cariprazine-treated patients and at least twice the rate of placebo. - Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms and akathisia. Adverse Reactions with an incidence of ≥ 2% and greater than placebo, at any dose are shown in TABLE 3. - Table 3. Adverse Reactions Occurring in ≥ 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials VRAYLAR: Cariprazine's Brand name Patients with Bipolar Mania The following findings are based on three placebo-controlled, 3-week bipolar mania trials with Cariprazine doses ranging from 3 to 12 mg once daily. - Adverse Reactions Associated with Discontinuation of Treatment: The only adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in Cariprazine-treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 12% of the patients who received Cariprazine discontinued treatment due to an adverse reaction, compared with 7% of placebo-treated patients in these trials. - Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness. Adverse Reactions with an incidence of ≥ 2% and greater than placebo at any dose are shown in TABLE 4. - Table 4. Adverse Reactions Occurring in ≥ 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials VRAYLAR: Cariprazine's Brand name Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Extrapyramidal Symptoms (EPS) and Akathisia In schizophrenia and bipolar mania trials, data were objectively collected using the Simpson Angus Rating Scale (SAS) for treatment-emergent EPS (parkinsonism) (SAS total score ≤ 3 at baseline and > 3 post-baseline) and the Barnes Akathisia Scale (BARS) for treatment-emergent akathisia (BARS total score ≤ 2 at baseline and > 2 post-baseline). In 6-week schizophrenia trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for Cariprazine-treated patients versus 8% for placebo-treated patients. These events led to discontinuation in 0.3% of Cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 11% for Cariprazine-treated patients versus 4% for placebo-treated patients. These events led to discontinuation in 0.5% of Cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of EPS is shown in TABLE 5. - Table 5. Incidence of EPS Compared to Placebo in 6-Week Schizophrenia Studies VRAYLAR: Cariprazine's Brand name In 3-week bipolar mania trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for Cariprazine-treated patients versus 12% for placebo-treated patients. These events led to a discontinuation in 1% of Cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 20% for Cariprazine-treated patients versus 5% for placebo-treated patients. These events led to discontinuation in 2% of Cariprazine-treated patients versus 0% of placebo-treated patients. The incidence of EPS is provided in TABLE 6. - Table 6. Incidence of EPS Compared to Placebo in 3-Week Bipolar Mania Trials VRAYLAR: Cariprazine's Brand name Cataracts In the long-term uncontrolled schizophrenia (48-week) and bipolar mania (16-week) trials, the incidence of cataracts was 0.1% and 0.2%, respectively. The development of cataracts was observed in nonclinical studies. The possibility of lenticular changes or cataracts cannot be excluded at this time. Vital Signs Changes There were no clinically meaningful differences between Cariprazine-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine blood pressure parameters except for an increase in supine diastolic blood pressure in the 9 - 12 mg/day Cariprazine-treated schizophrenia patients. Pooled data from 6-week schizophrenia and 3-week bipolar mania trials are shown in TABLES 7 and 8. - Table 7. Mean Change in Blood Pressure at Endpoint in 6-Week Schizophrenia Trials VRAYLAR: Cariprazine's Brand name - Table 8. Mean Change in Blood Pressure at Endpoint in 3-Week Bipolar Mania Trials VRAYLAR: Cariprazine's Brand name Changes in Laboratory Tests The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 6-week schizophrenia trials ranged between 1% and 2% for Cariprazine-treated patients, increasing with dose, and was 1% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 3-week bipolar mania trials ranged between 2% and 4% for Cariprazine-treated patients depending on dose group administered and 2% for placebo-treated patients. The proportions of patients with elevations of creatine phosphokinase (CPK) greater than 1000 U/L in 6-week schizophrenia trials ranged between 4% and 6% for Cariprazine-treated patients, increasing with dose, and was 4% for placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 3-week bipolar mania trials was about 4% in Cariprazine and placebo-treated patients. Other Adverse Reactions Observed During the Pre-marketing Evaluation of Cariprazine Adverse reactions listed below were reported by patients treated with Cariprazine at doses of ≥ 1.5 mg once daily within the database of 2758 Cariprazine-treated patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions that appear elsewhere in the Cariprazine label are not included. Reactions are further categorized by organ class and listed in order of decreasing frequency, according to the following definition: those occurring in at least 1/100 patients (frequent) ; those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare). - Gastrointestinal Disorders: Infrequent: gastroesophageal reflux disease, gastritis - Hepatobiliary Disorders: Rare: hepatitis - Metabolism and Nutrition Disorders: Frequent: decreased appetite; Infrequent: hyponatremia - Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis - Nervous System Disorders: Rare: ischemic stroke - Psychiatric Disorders: Infrequent: suicide attempts, suicide ideation; Rare: completed suicide - Renal and Urinary Disorders: Infrequent: pollakiuria - Skin and Subcutaneous Tissue Disorders: Infrequent: hyperhidrosis ## Postmarketing Experience There is limited information regarding Cariprazine Postmarketing Experience in the drug label. # Drug Interactions Drugs Having Clinically Important Interactions with Cariprazine - Table 9: Clinically Important Drug Interactions with Cariprazine VRAYLAR: Cariprazine's Brand name Drugs Having No Clinically Important Interactions with Cariprazine Based on in vitro studies, Cariprazine is unlikely to cause clinically significant pharmacokinetic drug interactions with substrates of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E, and CYP3A4, or OATP1B1, OATP1B3, BCRP, OCT2, OAT1 and OAT3. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Cariprazine during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit /. - Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There are no available data on Cariprazine use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. Based on animal data Cariprazine may cause fetal harm. Administration of Cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, Cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. - Clinical Considerations - Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. - Data - Animal Data Administration of Cariprazine to pregnant rats during the period of organogenesis at oral doses of 0.5, 2.5, and 7.5 mg/kg/day which are 0.2 to 3.5 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC of total Cariprazine (i.e. sum of Cariprazine, DCAR, and DDCAR) caused fetal developmental toxicity at all doses which included reduced body weight, decreased male anogenital distance and skeletal malformations of bent limb bones, scapula and humerus. These effects occurred in the absence or presence of maternal toxicity. Maternal toxicity, observed as a reduction in body weight and food consumption, occurred at doses 1.2 and 3.5-times the MRHD of 6 mg/kg/day based on AUC of total Cariprazine. At these doses, Cariprazine caused fetal external malformations (localized fetal thoracic edema), visceral variations (undeveloped/underdeveloped renal papillae and/or distended urethrae), and skeletal developmental variations (bent ribs, unossified sternebrae). Cariprazine had no effect on fetal survival. Administration of Cariprazine to pregnant rats during pregnancy and lactation at oral doses of 0.1, 0.3, and 1 mg/kg/day which are 0.03 to 0.4 times the MRHD of 6 mg/day based on AUC of total Cariprazine caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the MRHD of 6 mg/day based on AUC of total Cariprazine in absence of maternal toxicity. First generation pups also had pale, cold bodies and developmental delays (renal papillae not developed or underdeveloped and decreased auditory startle response in males). Reproductive performance of the first generation pups was unaffected; however, the second generation pups had clinical signs and lower body weight similar to these of the first generation pups. Administration of Cariprazine to pregnant rabbits during the period of organogenesis at oral doses of 0.1, 1, and 5 mg/kg/day, which are 0.02 to 4.6 times the MRHD of 6 mg/day based on AUC of total Cariprazine was not teratogenic. Maternal body weight and food consumption were decreased at 4.6 times the MRHD of 6 mg/day based on AUC of total Cariprazine; however, no adverse effects were observed on pregnancy parameters or reproductive organs. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cariprazine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cariprazine during labor and delivery. ### Nursing Mothers Lactation studies have not been conducted to assess the presence of Cariprazine in human milk, the effects on the breastfed infant, or the effects on milk production. Cariprazine is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Cariprazine and any potential adverse effects on the breastfed infant from Cariprazine or from the underlying maternal condition. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. Pediatric studies of Cariprazine have not been conducted. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. ### Geriatic Use Clinical trials of Cariprazine in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients with dementia-related psychosis treated with Cariprazine are at an increased risk of death compared to placebo. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. ### Gender There is no FDA guidance on the use of Cariprazine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cariprazine with respect to specific racial populations. ### Renal Impairment No dosage adjustment for Cariprazine is required in patients with mild to moderate (CrCL ≥ 30 mL/minute) renal impairment. Usage of Cariprazine is not recommended in patients with severe renal impairment (CrCL < 30 mL/minute). Cariprazine has not been evaluated in this patient population. ### Hepatic Impairment No dosage adjustment for Cariprazine is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9). Usage of Cariprazine is not recommended in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). Cariprazine has not been evaluated in this patient population. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cariprazine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cariprazine in patients who are immunocompromised. ### Specific Populations No dosage adjustment is required based on patient's age, sex, or race. These factors do not affect the pharmacokinetics of Cariprazine. - Controlled Substance Cariprazine is not a controlled substance. - Abuse Cariprazine has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance. - Dependence Cariprazine has not been systematically studied in animals or humans for its potential for physical dependence. # Administration and Monitoring ### Administration There is limited information regarding Cariprazine Administration in the drug label. ### Monitoring There is limited information regarding Cariprazine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Cariprazine and IV administrations. # Overdosage - Human Experience In pre-marketing clinical trials involving Cariprazine in approximately 5000 patients or healthy subjects, accidental acute overdosage (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day. - Management of Overdosage No specific antidotes for Cariprazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice. # Pharmacology ## Mechanism of Action The mechanism of action of Cariprazine in schizophrenia and bipolar I disorder is unknown. However, the efficacy of Cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug. ## Structure The active ingredient of Cariprazine HCl, an atypical antipsychotic. The chemical name is trans-N-{4-ethyl]cyclohexyl}-N',N'-dimethylurea hydrochloride; its empirical formula is C21H33Cl3N4O and its molecular weight is 463.9 g/mol. The chemical structure is: Cariprazine capsules are intended for oral administration only. Each hard gelatin capsule contains a white to off-white powder of Cariprazine HCl, which is equivalent to 1.5, 3, 4.5, or 6 mg of Cariprazine base. In addition, capsules include the following inactive ingredients: gelatin, magnesium stearate, pregelatinized starch, shellac, and titanium dioxide. Colorants include black iron oxide (1.5, 3, and 6 mg), FD&C Blue 1 (3, 4.5, and 6 mg), FD&C Red 3 (6 mg), FD&C Red 40 (3 and 4.5 mg), or yellow iron oxide (3 and 4.5 mg). ## Pharmacodynamics Cariprazine acts as a partial agonist at the dopamine D3 and D2 receptors with high binding affinity (Ki values 0.085 nM, and 0.49 nM (D2L) and 0.69 nM (D2S), respectively) and at the serotonin 5-HT1A receptors (Ki value 2.6 nM). Cariprazine acts as an antagonist at 5-HT2B and 5-HT2A receptors with high and moderate binding affinity (Ki values 0.58 nM and 18.8 nM respectively) as well as it binds to the histamine H1 receptors (Ki value 23.2 nM). Cariprazine shows lower binding affinity to the serotonin 5-HT2C and α1A- adrenergic receptors (Ki values 134 nM and 155 nM, respectively) and has no appreciable affinity for cholinergic muscarinic receptors (IC50>1000 nM). - Effect on QTc Interval At a dose three-times the maximum recommended dose, Cariprazine does not prolong the QTc interval to clinically relevant extent. ## Pharmacokinetics Cariprazine activity is thought to be mediated by Cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), which are pharmacologically equipotent to Cariprazine. After multiple dose administration of Cariprazine, mean Cariprazine and DCAR concentrations reached steady state at around Week 1 to Week 2 and mean DDCAR concentrations appeared to be approaching steady state at around Week 4 to Week 8 in a 12-week study (FIGURE 1). The half-lives based on time to reach steady state, estimated from the mean concentration-time curves, are 2 to 4 days for Cariprazine, and approximately 1 to 3 weeks for DDCAR. The time to reach steady state for the major active metabolite DDCAR was variable across patients, with some patients not achieving steady state at the end of the 12 week treatment. Mean concentrations of DCAR and DDCAR are approximately 30% and 400%, respectively, of Cariprazine concentrations by the end of 12-week treatment. After discontinuation of the drug, cariprazine, DCAR, and DDCAR plasma concentrations declined in a multi-exponential manner. Mean plasma concentrations of DDCAR decreased by about 50%, 1 week after the last dose and mean Cariprazine and DCAR concentration dropped by about 50% in about 1 day. There was an approximately 90% decline in plasma exposure within 1 week for Cariprazine and DCAR, and at about 4 weeks for DDCAR. Following a single dose of 1 mg of Cariprazine administration, DDCAR remained detectable 8 weeks post-dose. After multiple dosing of Cariprazine, plasma exposure of cariprazine, DCAR, and DDCAR, increases approximately proportionally over the therapeutic dose range. - Figure 1. Plasma Concentration (Mean ± SE)-Time Profile During and Following 12-weeks of Treatment with Cariprazine 6 mg/day(a) Absorption After single dose administration of Cariprazine, the peak plasma Cariprazine concentration occurred in approximately 3-6 hours. Administration of a single dose of 1.5 mg Cariprazine capsule with a high-fat meal did not significantly affect the Cmax and AUC of Cariprazine or DCAR. Distribution Cariprazine and its major active metabolites are highly bound (91 to 97%) to plasma proteins. Elimination - Metabolism Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to DCAR and DDCAR. DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite. - Excretion Following administration of 12.5 mg/day Cariprazine to patients with schizophrenia for 27 days, about 21% of the daily dose was found in urine, with approximately 1.2% of the daily dose was excreted in urine as unchanged Cariprazine. Studies in Specific Populations - Hepatic Impairment Compared to healthy subjects, patients with either mild or moderate hepatic impairment (Child-Pugh score between 5 and 9) had approximately 25% higher exposure (Cmax and AUC) for Cariprazine and approximately 45% lower exposure for the major active metabolites, DCAR and DDCAR, following a single dose of 1 mg Cariprazine or 0.5 mg Cariprazine for 14 days. - Renal Impairment Cariprazine and its major active metabolites are minimally excreted in urine. Pharmacokinetic analyses indicated no significant relationship between plasma clearance and creatinine clearance. - CYP2D6 Poor Metabolizers CYP2D6 poor metabolizer status does not have clinically relevant effect on pharmacokinetics of Cariprazine, DCAR, or DDCAR. - Age, Sex, Race Age, sex, or race does not have clinically relevant effect on pharmacokinetics of Cariprazine, DCAR, or DDCAR. Drug Interaction Studies - In vitro studies Cariprazine and its major active metabolites did not induce CYP1A2 and CYP3A4 enzymes and were weak inhibitors of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 in vitro. Cariprazine was also a weak inhibitor of CYP2C19, CYP2A6, and CYP2E1 in vitro. Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), the organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and the breast cancer resistance protein (BCRP). Cariprazine and its major active metabolites were poor or non-inhibitors of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. The major active metabolites were also poor or non-inhibitors of transporter P-gp although Cariprazine was probably a P-gp inhibitor based on the theoretical GI concentrations at high doses in vitro. - CYP3A4 inhibitors Coadministration of ketoconazole (400 mg/day), a strong CYP3A4 inhibitor, with Cariprazine (0.5 mg/day) increased Cariprazine Cmax and AUC(0-24h) by about 3.5-fold and 4-fold, respectively; increased DDCAR Cmax and AUC(0-24h) by about 1.5-fold; and decreased DCAR Cmax and AUC(0-24h) by about one-third. The impact of moderate CYP3A4 inhibitors has not been studied. - CYP3A4 inducers CYP3A4 is responsible for the formation and elimination of the active metabolites of Cariprazine. The effect of CYP3A4 inducers on the plasma exposure of Cariprazineand its major active metabolites has not been evaluated, and the net effect is unclear. - CYP2D6 inhibitors CYP2D6 inhibitors are not expected to influence pharmacokinetics of Cariprazine, DCAR or DDCAR based on the observations in CYP2D6 poor metabolizers. ## Nonclinical Toxicology - Carcinogenesis There was no increase in the incidence of tumors following daily oral administration of Cariprazine to rats for 2 years and to Tg.rasH2 mice for 6 months at doses which are up to 4 and 19 times respectively, the MRHD of 6 mg/day based on AUC of total Cariprazine, (i.e. sum of AUC values of Cariprazine, DCAR and DDCAR). Rats were administered Cariprazine at oral doses of 0.25, 0.75, and 2.5 (males)/1, 2.5, and 7.5 mg/kg/day (females) (which are 0.2 to 1.8 (males)/ 0.8 to 4.1 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. Tg.rasH2 mice were administered Cariprazine at oral doses of 1, 5, and 15 (males)/5, 15, and 50 mg/kg/day (females) which are 0.2 to 7.9 (males)/2.6 to 19 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. - Mutagenesis Cariprazine was not mutagenic in the in vitro bacterial reverse mutation assay, nor clastogenic in the in vitro human lymphocyte chromosomal aberration assay or in the in vivo mouse bone marrow micronucleus assay. However, Cariprazine increased the mutation frequency in the in vitro mouse lymphoma assay under conditions of metabolic activation. The major human metabolite DDCAR was not mutagenic in the in vitro bacterial reverse mutation assay, however, it was clastogenic and induced structural chromosomal aberration in the in vitro human lymphocyte chromosomal aberration assay. - Impairment of Fertility Cariprazine was administered orally to male and female rats before mating, through mating and up to day 7 of gestation at doses of 1, 3, and 10 mg/kg/day which are 1.6 to 16 times the MRHD of 6 mg/day based on mg/m2. In female rats, lower fertility and conception indices were observed at all dose levels which are equal to or higher than 1.6 times the MRHD of 6 mg/day based on mg/m2. No effects on male fertility were noted at any dose up to 4.3 times the MRHD of 6 mg/day based on AUC of total Cariprazine. Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following oral daily administration for 13 weeks and/or 1 year and retinal degeneration/atrophy in the rat following oral daily administration for 2 years. Cataract in the dog was observed at 4 mg/kg/day which is 7.1 (male) and 7.7 (female) times the MRHD of 6 mg/day based on AUC of total Cariprazine. The NOEL for cataract and retinal toxicity in the dog is 2 mg/kg/day which is 5 (males) to 3.6 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. Increased incidence and severity of retinal degeneration/atrophy in the rat occurred at all doses tested, including the low dose of 0.75 mg/kg/day, at total Cariprazine plasma levels less than clinical exposure (AUC) at the MRHD of 6 mg/day. Cataract was not observed in other repeat dose studies in pigmented mice or albino rats. Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures (AUC) of total Cariprazine. Phospholipidosis was not reversible at the end of the 1-2 month drug-free periods. Inflammation was observed in the lungs of dogs dosed daily for 1 year with a NOEL of 1 mg/kg/day which is 2.7 (males) and 1.7 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. No inflammation was observed at the end of 2-month drug free period following administration of 2 mg/kg/day which is 5 (males) and 3.6 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine; however, inflammation was still present at higher doses. Hypertrophy of the adrenal gland cortex was observed at clinically relevant total Cariprazine plasma concentrations in rats (females only) and mice following daily oral administration of Cariprazine for 2 years and 6 months, respectively. Reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were observed following daily oral administration of Cariprazine to dogs for 1 year. The NOEL was 2 mg/kg/day which is 5 (males) and 3.6 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. The relevance of these findings to human risk is unknown. # Clinical Studies The efficacy of Cariprazine for the treatment of schizophrenia was established in three, 6-week, randomized, double-blind, placebo-controlled trials in patients (aged 18 to 60 years) who met Diagnostic and Statistical Manual of Mental Disorders 4th edition, Text Revision (DSM-IV-TR) criteria for schizophrenia. An active control arm (risperidone or aripiprazole) was included in two trials to assess assay sensitivity. In all three trials, Cariprazine was superior to placebo. Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) rating scales were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: - PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). The PANSS total score may range from 30 to 210 with the higher score reflecting greater severity. - The CGI-S is a validated clinician-related scale that measures the patient's current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale. In each study, the primary endpoint was change from baseline in PANSS total score at the end of week 6. The change from baseline for Cariprazine and active control groups was compared to placebo. The results of the trials are shown in TABLE 10. The time course of efficacy results of Study 2 is shown in FIGURE 2. Study 1: In a 6-week, placebo-controlled trial (N = 711) involving three fixed doses of Cariprazine (1.5, 3, or 4.5 mg/day) and an active control (risperidone), all Cariprazine doses and the active control were superior to placebo on the PANSS total score and the CGI-S. Study 2: In a 6-week, placebo-controlled trial (N = 604) involving two fixed doses of Cariprazine (3 or 6 mg/day) and an active control (aripiprazole), both Cariprazine doses and the active control were superior to placebo on the PANSS total score and the CGI-S. Study 3: In a 6-week, placebo-controlled trial (N = 439) involving two flexible-dose range groups of Cariprazine (3 to 6 mg/day or 6 to 9 mg/day), both Cariprazine groups were superior to placebo on the PANSS total score and the CGI-S. The efficacy of Cariprazine was demonstrated at doses ranging from 1.5 to 9 mg/day compared to placebo. There was, however, a dose-related increase in certain adverse reactions, particularly above 6 mg. Therefore, the maximum recommended dose is 6 mg/day. Examination of population subgroups based on age (there were few patients over 55), sex, and race did not suggest any clear evidence of differential responsiveness. - Table 10. Primary Analysis Results from Schizophrenia Trials VRAYLAR: Cariprazine's Brand name - Figure 2 Change from Baseline in PANSS total score by weekly visits (Study 2) VRAYLAR: Cariprazine's Brand name The efficacy of Cariprazine in the acute treatment of bipolar mania was established in three, 3-week placebo-controlled trials in patients (mean age of 39 years, range 18 to 65 years) who met DSM-IV-TR criteria for bipolar 1 disorder with manic or mixed episodes with or without psychotic features. In all three trials, Cariprazine was superior to placebo. Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity scale (CGI-S) were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: The YMRS is an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology. YMRS total score may range from 0 to 60 with a higher score reflecting greater severity. The CGI-S is validated clinician-related scale that measures the patient's current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale. In each study, the primary endpoint was decrease from baseline in YMRS total score at the end of week 3. The change from baseline for each Cariprazine dose group was compared to placebo. The results of the trials are shown in TABLE 11. The time course of efficacy results is shown in FIGURE 3. Study 1: In a 3-week, placebo-controlled trial (N = 492) involving two flexible-dose range groups of Cariprazine (3 to 6 mg/day or 6 to 12 mg/day), both Cariprazine dose groups were superior to placebo on the YMRS total score and the CGI-S. The 6 to 12 mg/day dose group showed no additional advantage. Study 2: In a 3-week, placebo-controlled trial (N = 235) involving a flexible-dose range of Cariprazine (3 to 12 mg/day), Cariprazine was superior to placebo on the YMRS total score and the CGI-S. Study 3: In a 3-week, placebo-controlled trial (N = 310) involving a flexible-dose range of Cariprazine (3 to 12 mg/day), Cariprazine was superior to placebo on the YMRS total score and the CGI-S. The efficacy of Cariprazine was established at doses ranging from 3 to 12 mg/day. Doses above 6 mg did not appear to have additional benefit over lower doses (TABLE 11) and there was a dose-related increase in certain adverse reactions. Therefore, the maximum recommended dose is 6 mg/day. Examination of population subgroups based on age (there were few patients over 55), sex, and race did not suggest any clear evidence of differential responsiveness. - Table 11. Primary Analysis Results from Manic or Mixed Episodes Associated with Bipolar I Disorder Trials VRAYLAR: Cariprazine's Brand name - Figure 3 Change from Baseline in YMRS total score by study visit (Study 1) VRAYLAR: Cariprazine's Brand name # How Supplied Cariprazine capsules are supplied as follows: - 1.5 mg capsules: White cap and body imprinted with “FL 1.5” - 3 mg capsules: Green to blue-green cap and white body imprinted with “FL 3” - 4.5 mg capsules: Green to blue-green cap and body imprinted with “FL 4.5” - 6 mg capsules: Purple cap and white body imprinted with “FL 6” ## Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Protect 3 mg and 4.5 mg capsules from light to prevent potential color fading. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Physicians are advised to discuss with patients for whom they prescribe Cariprazine all relevant safety information including, but not limited to, the following: - Dosage and Administration Advise patients that Cariprazine can be taken with or without food. Counsel them on the importance of following dosage escalation instructions. - Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. - Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur. - Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight. - Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking Cariprazine. - Orthostatic Hypotension Counsel patients on the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment or increases in dose. - Interference with Cognitive and Motor Performance Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that Cariprazine therapy does not affect them adversely. - Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration. - Concomitant Medications Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs since there is a potential for interactions. - Pregnancy Advise patients that third trimester use of Cariprazine may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy. - Pregnancy Registry: Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Cariprazine during pregnancy. # Precautions with Alcohol Alcohol-Cariprazine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names VRAYLAR™ # Look-Alike Drug Names There is limited information regarding Cariprazine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Cariprazine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [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 Cariprazine is an atypical antipsychotic that is FDA approved for the treatment of patients with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include extrapyramidal symptoms and akathisia in Schizophrenia patients and extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness in patients with Bipolar mania (≥5%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Cariprazine is indicated for the: - Treatment of schizophrenia - Acute treatment of manic or mixed episodes associated with bipolar I disorder Cariprazine is given orally once daily and can be taken with or without food. Because of the long half-life of Cariprazine and its active metabolites, changes in dose will not be fully reflected in plasma for several weeks. Prescribers should monitor patients for adverse reactions and treatment response for several weeks after starting Cariprazine and after each dosage change. The maximum recommended dose is 6 mg daily. In short-term controlled trials, dosages above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. - Schizophrenia The recommended dose range is 1.5 mg to 6 mg once daily. The starting dose of Cariprazine is 1.5 mg. The dosage can be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. - Manic or Mixed Episodes Associated with Bipolar I Disorder The recommended dose range is 3 mg to 6 mg once daily. The starting dose of Cariprazine is 1.5 mg and should be increased to 3 mg on Day 2. Depending upon clinical response and tolerability, further dose adjustments can be made in 1.5 mg or 3 mg increments. - Dosage Adjustments for CYP3A4 Inhibitors and Inducers CYP3A4 is responsible for the formation and elimination of the major active metabolites of Cariprazine. - Dosage recommendation for patients initiating a strong CYP3A4 inhibitor while on a stable dose of Cariprazine: If a strong CYP3A4 inhibitor is initiated, reduce the current dosage of Cariprazine by half. For patients taking 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking 1.5 mg daily, the dosing regimen should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, Cariprazine dosage may need to be increased. - Dosage recommendation for patients initiating Cariprazine therapy while already on a strong CYP3A4 inhibitor: Patients should be administered 1.5 mg of Cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, Cariprazine dosage may need to be increased. - Dosage recommendation for patients concomitantly taking Cariprazine with CYP3A4 inducers:Concomitant use of Cariprazine and a CYP3A4 inducer has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear. - Treatment Discontinuation Following discontinuation of Cariprazine, the decline in plasma concentrations of active drug and metabolites may not be immediately reflected in patients' clinical symptoms; the plasma concentration of Cariprazine and its active metabolites will decline by 50% in ~1 week. There are no systematically collected data to specifically address switching patients from Cariprazine to other antipsychotics or concerning concomitant administration with other antipsychotics. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cariprazine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cariprazine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. Pediatric studies of Cariprazine have not been conducted. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Cariprazine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Cariprazine in pediatric patients. # Contraindications Cariprazine is contraindicated in patients with history of a hypersensitivity reaction to Cariprazine. Reactions have ranged from rash, pruritus, urticaria, and events suggestive of angioedema (e.g., swollen tongue, lip swelling, face edema, pharyngeal edema, and swelling face). # Warnings Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue Cariprazine and provide intensive symptomatic treatment and monitoring. Cariprazine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including Cariprazine. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. There is no known treatment for tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Given these considerations, Cariprazine should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on Cariprazine, drug discontinuation should be considered. However, some patients may require treatment with Cariprazine despite the presence of the syndrome. Adverse events may first appear several weeks after the initiation of Cariprazine treatment, probably because plasma levels of Cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures. Monitor for adverse reactions, including EPS or akathisia, and patient response for several weeks after a patient has begun Cariprazine and after each dosage increase. Consider reducing the dose or discontinuing the drug. Atypical antipsychotic drugs, including Cariprazine, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile. - Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment. - Schizophrenia In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with Cariprazine and placebo. In the long-term, open-label schizophrenia studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels ( ≥6.5%). - Bipolar Mania In the 3-week, placebo-controlled trials of adult patients with bipolar disorder, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with Cariprazine and placebo. In the long-term, open-label bipolar disorder studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥6.5%). - Dyslipidemia Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. - Schizophrenia In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with Cariprazine and placebo. - Bipolar Mania In the 3-week, placebo-controlled trials of adult patients with bipolar disorder, the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with Cariprazine and placebo. - Weight Gain Weight gain has been observed with use of atypical antipsychotics, including Cariprazine. Monitor weight at baseline and frequently thereafter. TABLES 1 and 2 show the change in body weight occurring from baseline to endpoint in 6-week schizophrenia and 3-week bipolar mania trials. - Table 1. Change in Body Weight (kg) in 6-Week Schizophrenia Trials VRAYLAR: Cariprazine's Brand name - Table 2. Change in Body Weight (kg) in 3-Week Bipolar Mania Trials VRAYLAR: Cariprazine's Brand name In long-term, uncontrolled trials with Cariprazine in schizophrenia, the mean changes from baseline in weight at 12, 24, and 48 weeks were 1.2 kg, 1.7 kg, and 2.5 kg, respectively. Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including Cariprazine. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Cariprazine at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue Cariprazine in patients with absolute neutrophil count < 1000/mm3 and follow their WBC until recovery. Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Symptomatic orthostatic hypotension was infrequent in trials of Cariprazine and was not more frequent on Cariprazine than placebo. Syncope was not observed. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. Cariprazine has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials. Like other antipsychotic drugs, Cariprazine may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients. Cariprazine, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In 6-week schizophrenia trials, somnolence (hypersomnia, sedation, and somnolence) was reported in 7% of Cariprazine-treated patients compared to 6% of placebo-treated patients. In 3-week bipolar mania trials, somnolence was reported in 8% of Cariprazine-treated patients compared to 4% of placebo-treated patients. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with Cariprazine does not affect them adversely. Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use Cariprazine with caution in patient who may experience these conditions. Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with Cariprazine. Cariprazine and other antipsychotic drugs should be used cautiously in patients at risk for aspiration. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are discussed in more detail in other sections of the labeling: - Increased Mortality in Elderly Patients with Dementia-Related Psychosis - Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis - Neuroleptic Malignant Syndrome - Tardive Dyskinesia - Late Occurring Adverse Reactions - Metabolic Changes - Leukopenia, Neutropenia, and Agranulocytosis - Orthostatic Hypotension and Syncope - Seizures - Potential for Cognitive and Motor Impairment - Body Temperature Dysregulation - Dysphagia 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 information below is derived from the clinical trial database for Cariprazine, consisting of 1733 patients with schizophrenia (aged 18 to 65) and 1025 patients with manic or mixed episodes associated with bipolar I disorder (aged 18 to 65) exposed to one or more doses with a total experience of 566.5 patient-years. Of these patients, 1317 participated in placebo-controlled, 6-week schizophrenia trials with doses ranging from 1.5 mg to 12 mg/day and 623 participated in placebo-controlled, 3-week bipolar mania trials with doses ranging from 3 mg to 12 mg/day. A total of 364 Cariprazine-treated patients had at least 24 weeks of exposure and 239 Cariprazine-treated patients had at least 48 weeks of exposure. Patients with Schizophrenia The following findings are based on four placebo-controlled, 6-week schizophrenia trials with Cariprazine doses ranging from 1.5 to 12 mg once daily. - Adverse Reactions Associated with Discontinuation of Treatment: There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in Cariprazine-treated patients and at least twice the rate of placebo. - Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms and akathisia. Adverse Reactions with an incidence of ≥ 2% and greater than placebo, at any dose are shown in TABLE 3. - Table 3. Adverse Reactions Occurring in ≥ 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials VRAYLAR: Cariprazine's Brand name Patients with Bipolar Mania The following findings are based on three placebo-controlled, 3-week bipolar mania trials with Cariprazine doses ranging from 3 to 12 mg once daily. - Adverse Reactions Associated with Discontinuation of Treatment: The only adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in Cariprazine-treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 12% of the patients who received Cariprazine discontinued treatment due to an adverse reaction, compared with 7% of placebo-treated patients in these trials. - Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness. Adverse Reactions with an incidence of ≥ 2% and greater than placebo at any dose are shown in TABLE 4. - Table 4. Adverse Reactions Occurring in ≥ 2% of Cariprazine-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials VRAYLAR: Cariprazine's Brand name Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Extrapyramidal Symptoms (EPS) and Akathisia In schizophrenia and bipolar mania trials, data were objectively collected using the Simpson Angus Rating Scale (SAS) for treatment-emergent EPS (parkinsonism) (SAS total score ≤ 3 at baseline and > 3 post-baseline) and the Barnes Akathisia Scale (BARS) for treatment-emergent akathisia (BARS total score ≤ 2 at baseline and > 2 post-baseline). In 6-week schizophrenia trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for Cariprazine-treated patients versus 8% for placebo-treated patients. These events led to discontinuation in 0.3% of Cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 11% for Cariprazine-treated patients versus 4% for placebo-treated patients. These events led to discontinuation in 0.5% of Cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of EPS is shown in TABLE 5. - Table 5. Incidence of EPS Compared to Placebo in 6-Week Schizophrenia Studies VRAYLAR: Cariprazine's Brand name In 3-week bipolar mania trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for Cariprazine-treated patients versus 12% for placebo-treated patients. These events led to a discontinuation in 1% of Cariprazine-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 20% for Cariprazine-treated patients versus 5% for placebo-treated patients. These events led to discontinuation in 2% of Cariprazine-treated patients versus 0% of placebo-treated patients. The incidence of EPS is provided in TABLE 6. - Table 6. Incidence of EPS Compared to Placebo in 3-Week Bipolar Mania Trials VRAYLAR: Cariprazine's Brand name Cataracts In the long-term uncontrolled schizophrenia (48-week) and bipolar mania (16-week) trials, the incidence of cataracts was 0.1% and 0.2%, respectively. The development of cataracts was observed in nonclinical studies. The possibility of lenticular changes or cataracts cannot be excluded at this time. Vital Signs Changes There were no clinically meaningful differences between Cariprazine-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine blood pressure parameters except for an increase in supine diastolic blood pressure in the 9 - 12 mg/day Cariprazine-treated schizophrenia patients. Pooled data from 6-week schizophrenia and 3-week bipolar mania trials are shown in TABLES 7 and 8. - Table 7. Mean Change in Blood Pressure at Endpoint in 6-Week Schizophrenia Trials VRAYLAR: Cariprazine's Brand name - Table 8. Mean Change in Blood Pressure at Endpoint in 3-Week Bipolar Mania Trials VRAYLAR: Cariprazine's Brand name Changes in Laboratory Tests The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 6-week schizophrenia trials ranged between 1% and 2% for Cariprazine-treated patients, increasing with dose, and was 1% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 3-week bipolar mania trials ranged between 2% and 4% for Cariprazine-treated patients depending on dose group administered and 2% for placebo-treated patients. The proportions of patients with elevations of creatine phosphokinase (CPK) greater than 1000 U/L in 6-week schizophrenia trials ranged between 4% and 6% for Cariprazine-treated patients, increasing with dose, and was 4% for placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 3-week bipolar mania trials was about 4% in Cariprazine and placebo-treated patients. Other Adverse Reactions Observed During the Pre-marketing Evaluation of Cariprazine Adverse reactions listed below were reported by patients treated with Cariprazine at doses of ≥ 1.5 mg once daily within the database of 2758 Cariprazine-treated patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions that appear elsewhere in the Cariprazine label are not included. Reactions are further categorized by organ class and listed in order of decreasing frequency, according to the following definition: those occurring in at least 1/100 patients (frequent) [only those not already listed in the tabulated results from placebo-controlled studies appear in this listing]; those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare). - Gastrointestinal Disorders: Infrequent: gastroesophageal reflux disease, gastritis - Hepatobiliary Disorders: Rare: hepatitis - Metabolism and Nutrition Disorders: Frequent: decreased appetite; Infrequent: hyponatremia - Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis - Nervous System Disorders: Rare: ischemic stroke - Psychiatric Disorders: Infrequent: suicide attempts, suicide ideation; Rare: completed suicide - Renal and Urinary Disorders: Infrequent: pollakiuria - Skin and Subcutaneous Tissue Disorders: Infrequent: hyperhidrosis ## Postmarketing Experience There is limited information regarding Cariprazine Postmarketing Experience in the drug label. # Drug Interactions Drugs Having Clinically Important Interactions with Cariprazine - Table 9: Clinically Important Drug Interactions with Cariprazine VRAYLAR: Cariprazine's Brand name Drugs Having No Clinically Important Interactions with Cariprazine Based on in vitro studies, Cariprazine is unlikely to cause clinically significant pharmacokinetic drug interactions with substrates of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E, and CYP3A4, or OATP1B1, OATP1B3, BCRP, OCT2, OAT1 and OAT3. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Cariprazine during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. - Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There are no available data on Cariprazine use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. Based on animal data Cariprazine may cause fetal harm. Administration of Cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, Cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. - Clinical Considerations - Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. - Data - Animal Data Administration of Cariprazine to pregnant rats during the period of organogenesis at oral doses of 0.5, 2.5, and 7.5 mg/kg/day which are 0.2 to 3.5 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC of total Cariprazine (i.e. sum of Cariprazine, DCAR, and DDCAR) caused fetal developmental toxicity at all doses which included reduced body weight, decreased male anogenital distance and skeletal malformations of bent limb bones, scapula and humerus. These effects occurred in the absence or presence of maternal toxicity. Maternal toxicity, observed as a reduction in body weight and food consumption, occurred at doses 1.2 and 3.5-times the MRHD of 6 mg/kg/day based on AUC of total Cariprazine. At these doses, Cariprazine caused fetal external malformations (localized fetal thoracic edema), visceral variations (undeveloped/underdeveloped renal papillae and/or distended urethrae), and skeletal developmental variations (bent ribs, unossified sternebrae). Cariprazine had no effect on fetal survival. Administration of Cariprazine to pregnant rats during pregnancy and lactation at oral doses of 0.1, 0.3, and 1 mg/kg/day which are 0.03 to 0.4 times the MRHD of 6 mg/day based on AUC of total Cariprazine caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the MRHD of 6 mg/day based on AUC of total Cariprazine in absence of maternal toxicity. First generation pups also had pale, cold bodies and developmental delays (renal papillae not developed or underdeveloped and decreased auditory startle response in males). Reproductive performance of the first generation pups was unaffected; however, the second generation pups had clinical signs and lower body weight similar to these of the first generation pups. Administration of Cariprazine to pregnant rabbits during the period of organogenesis at oral doses of 0.1, 1, and 5 mg/kg/day, which are 0.02 to 4.6 times the MRHD of 6 mg/day based on AUC of total Cariprazine was not teratogenic. Maternal body weight and food consumption were decreased at 4.6 times the MRHD of 6 mg/day based on AUC of total Cariprazine; however, no adverse effects were observed on pregnancy parameters or reproductive organs. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cariprazine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Cariprazine during labor and delivery. ### Nursing Mothers Lactation studies have not been conducted to assess the presence of Cariprazine in human milk, the effects on the breastfed infant, or the effects on milk production. Cariprazine is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Cariprazine and any potential adverse effects on the breastfed infant from Cariprazine or from the underlying maternal condition. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. Pediatric studies of Cariprazine have not been conducted. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. ### Geriatic Use Clinical trials of Cariprazine in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients with dementia-related psychosis treated with Cariprazine are at an increased risk of death compared to placebo. Cariprazine is not approved for the treatment of patients with dementia-related psychosis. ### Gender There is no FDA guidance on the use of Cariprazine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Cariprazine with respect to specific racial populations. ### Renal Impairment No dosage adjustment for Cariprazine is required in patients with mild to moderate (CrCL ≥ 30 mL/minute) renal impairment. Usage of Cariprazine is not recommended in patients with severe renal impairment (CrCL < 30 mL/minute). Cariprazine has not been evaluated in this patient population. ### Hepatic Impairment No dosage adjustment for Cariprazine is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9). Usage of Cariprazine is not recommended in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). Cariprazine has not been evaluated in this patient population. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Cariprazine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Cariprazine in patients who are immunocompromised. ### Specific Populations No dosage adjustment is required based on patient's age, sex, or race. These factors do not affect the pharmacokinetics of Cariprazine. - Controlled Substance Cariprazine is not a controlled substance. - Abuse Cariprazine has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance. - Dependence Cariprazine has not been systematically studied in animals or humans for its potential for physical dependence. # Administration and Monitoring ### Administration There is limited information regarding Cariprazine Administration in the drug label. ### Monitoring There is limited information regarding Cariprazine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Cariprazine and IV administrations. # Overdosage - Human Experience In pre-marketing clinical trials involving Cariprazine in approximately 5000 patients or healthy subjects, accidental acute overdosage (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day. - Management of Overdosage No specific antidotes for Cariprazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice. # Pharmacology ## Mechanism of Action The mechanism of action of Cariprazine in schizophrenia and bipolar I disorder is unknown. However, the efficacy of Cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug. ## Structure The active ingredient of Cariprazine HCl, an atypical antipsychotic. The chemical name is trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N',N'-dimethylurea hydrochloride; its empirical formula is C21H33Cl3N4O and its molecular weight is 463.9 g/mol. The chemical structure is: Cariprazine capsules are intended for oral administration only. Each hard gelatin capsule contains a white to off-white powder of Cariprazine HCl, which is equivalent to 1.5, 3, 4.5, or 6 mg of Cariprazine base. In addition, capsules include the following inactive ingredients: gelatin, magnesium stearate, pregelatinized starch, shellac, and titanium dioxide. Colorants include black iron oxide (1.5, 3, and 6 mg), FD&C Blue 1 (3, 4.5, and 6 mg), FD&C Red 3 (6 mg), FD&C Red 40 (3 and 4.5 mg), or yellow iron oxide (3 and 4.5 mg). ## Pharmacodynamics Cariprazine acts as a partial agonist at the dopamine D3 and D2 receptors with high binding affinity (Ki values 0.085 nM, and 0.49 nM (D2L) and 0.69 nM (D2S), respectively) and at the serotonin 5-HT1A receptors (Ki value 2.6 nM). Cariprazine acts as an antagonist at 5-HT2B and 5-HT2A receptors with high and moderate binding affinity (Ki values 0.58 nM and 18.8 nM respectively) as well as it binds to the histamine H1 receptors (Ki value 23.2 nM). Cariprazine shows lower binding affinity to the serotonin 5-HT2C and α1A- adrenergic receptors (Ki values 134 nM and 155 nM, respectively) and has no appreciable affinity for cholinergic muscarinic receptors (IC50>1000 nM). - Effect on QTc Interval At a dose three-times the maximum recommended dose, Cariprazine does not prolong the QTc interval to clinically relevant extent. ## Pharmacokinetics Cariprazine activity is thought to be mediated by Cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), which are pharmacologically equipotent to Cariprazine. After multiple dose administration of Cariprazine, mean Cariprazine and DCAR concentrations reached steady state at around Week 1 to Week 2 and mean DDCAR concentrations appeared to be approaching steady state at around Week 4 to Week 8 in a 12-week study (FIGURE 1). The half-lives based on time to reach steady state, estimated from the mean concentration-time curves, are 2 to 4 days for Cariprazine, and approximately 1 to 3 weeks for DDCAR. The time to reach steady state for the major active metabolite DDCAR was variable across patients, with some patients not achieving steady state at the end of the 12 week treatment. Mean concentrations of DCAR and DDCAR are approximately 30% and 400%, respectively, of Cariprazine concentrations by the end of 12-week treatment. After discontinuation of the drug, cariprazine, DCAR, and DDCAR plasma concentrations declined in a multi-exponential manner. Mean plasma concentrations of DDCAR decreased by about 50%, 1 week after the last dose and mean Cariprazine and DCAR concentration dropped by about 50% in about 1 day. There was an approximately 90% decline in plasma exposure within 1 week for Cariprazine and DCAR, and at about 4 weeks for DDCAR. Following a single dose of 1 mg of Cariprazine administration, DDCAR remained detectable 8 weeks post-dose. After multiple dosing of Cariprazine, plasma exposure of cariprazine, DCAR, and DDCAR, increases approximately proportionally over the therapeutic dose range. - Figure 1. Plasma Concentration (Mean ± SE)-Time Profile During and Following 12-weeks of Treatment with Cariprazine 6 mg/day(a) Absorption After single dose administration of Cariprazine, the peak plasma Cariprazine concentration occurred in approximately 3-6 hours. Administration of a single dose of 1.5 mg Cariprazine capsule with a high-fat meal did not significantly affect the Cmax and AUC of Cariprazine or DCAR. Distribution Cariprazine and its major active metabolites are highly bound (91 to 97%) to plasma proteins. Elimination - Metabolism Cariprazine is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to DCAR and DDCAR. DCAR is further metabolized into DDCAR by CYP3A4 and CYP2D6. DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite. - Excretion Following administration of 12.5 mg/day Cariprazine to patients with schizophrenia for 27 days, about 21% of the daily dose was found in urine, with approximately 1.2% of the daily dose was excreted in urine as unchanged Cariprazine. Studies in Specific Populations - Hepatic Impairment Compared to healthy subjects, patients with either mild or moderate hepatic impairment (Child-Pugh score between 5 and 9) had approximately 25% higher exposure (Cmax and AUC) for Cariprazine and approximately 45% lower exposure for the major active metabolites, DCAR and DDCAR, following a single dose of 1 mg Cariprazine or 0.5 mg Cariprazine for 14 days. - Renal Impairment Cariprazine and its major active metabolites are minimally excreted in urine. Pharmacokinetic analyses indicated no significant relationship between plasma clearance and creatinine clearance. - CYP2D6 Poor Metabolizers CYP2D6 poor metabolizer status does not have clinically relevant effect on pharmacokinetics of Cariprazine, DCAR, or DDCAR. - Age, Sex, Race Age, sex, or race does not have clinically relevant effect on pharmacokinetics of Cariprazine, DCAR, or DDCAR. Drug Interaction Studies - In vitro studies Cariprazine and its major active metabolites did not induce CYP1A2 and CYP3A4 enzymes and were weak inhibitors of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 in vitro. Cariprazine was also a weak inhibitor of CYP2C19, CYP2A6, and CYP2E1 in vitro. Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), the organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and the breast cancer resistance protein (BCRP). Cariprazine and its major active metabolites were poor or non-inhibitors of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. The major active metabolites were also poor or non-inhibitors of transporter P-gp although Cariprazine was probably a P-gp inhibitor based on the theoretical GI concentrations at high doses in vitro. - CYP3A4 inhibitors Coadministration of ketoconazole (400 mg/day), a strong CYP3A4 inhibitor, with Cariprazine (0.5 mg/day) increased Cariprazine Cmax and AUC(0-24h) by about 3.5-fold and 4-fold, respectively; increased DDCAR Cmax and AUC(0-24h) by about 1.5-fold; and decreased DCAR Cmax and AUC(0-24h) by about one-third. The impact of moderate CYP3A4 inhibitors has not been studied. - CYP3A4 inducers CYP3A4 is responsible for the formation and elimination of the active metabolites of Cariprazine. The effect of CYP3A4 inducers on the plasma exposure of Cariprazineand its major active metabolites has not been evaluated, and the net effect is unclear. - CYP2D6 inhibitors CYP2D6 inhibitors are not expected to influence pharmacokinetics of Cariprazine, DCAR or DDCAR based on the observations in CYP2D6 poor metabolizers. ## Nonclinical Toxicology - Carcinogenesis There was no increase in the incidence of tumors following daily oral administration of Cariprazine to rats for 2 years and to Tg.rasH2 mice for 6 months at doses which are up to 4 and 19 times respectively, the MRHD of 6 mg/day based on AUC of total Cariprazine, (i.e. sum of AUC values of Cariprazine, DCAR and DDCAR). Rats were administered Cariprazine at oral doses of 0.25, 0.75, and 2.5 (males)/1, 2.5, and 7.5 mg/kg/day (females) (which are 0.2 to 1.8 (males)/ 0.8 to 4.1 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. Tg.rasH2 mice were administered Cariprazine at oral doses of 1, 5, and 15 (males)/5, 15, and 50 mg/kg/day (females) which are 0.2 to 7.9 (males)/2.6 to 19 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. - Mutagenesis Cariprazine was not mutagenic in the in vitro bacterial reverse mutation assay, nor clastogenic in the in vitro human lymphocyte chromosomal aberration assay or in the in vivo mouse bone marrow micronucleus assay. However, Cariprazine increased the mutation frequency in the in vitro mouse lymphoma assay under conditions of metabolic activation. The major human metabolite DDCAR was not mutagenic in the in vitro bacterial reverse mutation assay, however, it was clastogenic and induced structural chromosomal aberration in the in vitro human lymphocyte chromosomal aberration assay. - Impairment of Fertility Cariprazine was administered orally to male and female rats before mating, through mating and up to day 7 of gestation at doses of 1, 3, and 10 mg/kg/day which are 1.6 to 16 times the MRHD of 6 mg/day based on mg/m2. In female rats, lower fertility and conception indices were observed at all dose levels which are equal to or higher than 1.6 times the MRHD of 6 mg/day based on mg/m2. No effects on male fertility were noted at any dose up to 4.3 times the MRHD of 6 mg/day based on AUC of total Cariprazine. Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following oral daily administration for 13 weeks and/or 1 year and retinal degeneration/atrophy in the rat following oral daily administration for 2 years. Cataract in the dog was observed at 4 mg/kg/day which is 7.1 (male) and 7.7 (female) times the MRHD of 6 mg/day based on AUC of total Cariprazine. The NOEL for cataract and retinal toxicity in the dog is 2 mg/kg/day which is 5 (males) to 3.6 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. Increased incidence and severity of retinal degeneration/atrophy in the rat occurred at all doses tested, including the low dose of 0.75 mg/kg/day, at total Cariprazine plasma levels less than clinical exposure (AUC) at the MRHD of 6 mg/day. Cataract was not observed in other repeat dose studies in pigmented mice or albino rats. Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures (AUC) of total Cariprazine. Phospholipidosis was not reversible at the end of the 1-2 month drug-free periods. Inflammation was observed in the lungs of dogs dosed daily for 1 year with a NOEL of 1 mg/kg/day which is 2.7 (males) and 1.7 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. No inflammation was observed at the end of 2-month drug free period following administration of 2 mg/kg/day which is 5 (males) and 3.6 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine; however, inflammation was still present at higher doses. Hypertrophy of the adrenal gland cortex was observed at clinically relevant total Cariprazine plasma concentrations in rats (females only) and mice following daily oral administration of Cariprazine for 2 years and 6 months, respectively. Reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were observed following daily oral administration of Cariprazine to dogs for 1 year. The NOEL was 2 mg/kg/day which is 5 (males) and 3.6 (females) times the MRHD of 6 mg/day based on AUC of total Cariprazine. The relevance of these findings to human risk is unknown. # Clinical Studies The efficacy of Cariprazine for the treatment of schizophrenia was established in three, 6-week, randomized, double-blind, placebo-controlled trials in patients (aged 18 to 60 years) who met Diagnostic and Statistical Manual of Mental Disorders 4th edition, Text Revision (DSM-IV-TR) criteria for schizophrenia. An active control arm (risperidone or aripiprazole) was included in two trials to assess assay sensitivity. In all three trials, Cariprazine was superior to placebo. Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) rating scales were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: - PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme). The PANSS total score may range from 30 to 210 with the higher score reflecting greater severity. - The CGI-S is a validated clinician-related scale that measures the patient's current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale. In each study, the primary endpoint was change from baseline in PANSS total score at the end of week 6. The change from baseline for Cariprazine and active control groups was compared to placebo. The results of the trials are shown in TABLE 10. The time course of efficacy results of Study 2 is shown in FIGURE 2. Study 1: In a 6-week, placebo-controlled trial (N = 711) involving three fixed doses of Cariprazine (1.5, 3, or 4.5 mg/day) and an active control (risperidone), all Cariprazine doses and the active control were superior to placebo on the PANSS total score and the CGI-S. Study 2: In a 6-week, placebo-controlled trial (N = 604) involving two fixed doses of Cariprazine (3 or 6 mg/day) and an active control (aripiprazole), both Cariprazine doses and the active control were superior to placebo on the PANSS total score and the CGI-S. Study 3: In a 6-week, placebo-controlled trial (N = 439) involving two flexible-dose range groups of Cariprazine (3 to 6 mg/day or 6 to 9 mg/day), both Cariprazine groups were superior to placebo on the PANSS total score and the CGI-S. The efficacy of Cariprazine was demonstrated at doses ranging from 1.5 to 9 mg/day compared to placebo. There was, however, a dose-related increase in certain adverse reactions, particularly above 6 mg. Therefore, the maximum recommended dose is 6 mg/day. Examination of population subgroups based on age (there were few patients over 55), sex, and race did not suggest any clear evidence of differential responsiveness. - Table 10. Primary Analysis Results from Schizophrenia Trials VRAYLAR: Cariprazine's Brand name - Figure 2 Change from Baseline in PANSS total score by weekly visits (Study 2) VRAYLAR: Cariprazine's Brand name The efficacy of Cariprazine in the acute treatment of bipolar mania was established in three, 3-week placebo-controlled trials in patients (mean age of 39 years, range 18 to 65 years) who met DSM-IV-TR criteria for bipolar 1 disorder with manic or mixed episodes with or without psychotic features. In all three trials, Cariprazine was superior to placebo. Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity scale (CGI-S) were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial: The YMRS is an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology. YMRS total score may range from 0 to 60 with a higher score reflecting greater severity. The CGI-S is validated clinician-related scale that measures the patient's current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale. In each study, the primary endpoint was decrease from baseline in YMRS total score at the end of week 3. The change from baseline for each Cariprazine dose group was compared to placebo. The results of the trials are shown in TABLE 11. The time course of efficacy results is shown in FIGURE 3. Study 1: In a 3-week, placebo-controlled trial (N = 492) involving two flexible-dose range groups of Cariprazine (3 to 6 mg/day or 6 to 12 mg/day), both Cariprazine dose groups were superior to placebo on the YMRS total score and the CGI-S. The 6 to 12 mg/day dose group showed no additional advantage. Study 2: In a 3-week, placebo-controlled trial (N = 235) involving a flexible-dose range of Cariprazine (3 to 12 mg/day), Cariprazine was superior to placebo on the YMRS total score and the CGI-S. Study 3: In a 3-week, placebo-controlled trial (N = 310) involving a flexible-dose range of Cariprazine (3 to 12 mg/day), Cariprazine was superior to placebo on the YMRS total score and the CGI-S. The efficacy of Cariprazine was established at doses ranging from 3 to 12 mg/day. Doses above 6 mg did not appear to have additional benefit over lower doses (TABLE 11) and there was a dose-related increase in certain adverse reactions. Therefore, the maximum recommended dose is 6 mg/day. Examination of population subgroups based on age (there were few patients over 55), sex, and race did not suggest any clear evidence of differential responsiveness. - Table 11. Primary Analysis Results from Manic or Mixed Episodes Associated with Bipolar I Disorder Trials VRAYLAR: Cariprazine's Brand name - Figure 3 Change from Baseline in YMRS total score by study visit (Study 1) VRAYLAR: Cariprazine's Brand name # How Supplied Cariprazine capsules are supplied as follows: - 1.5 mg capsules: White cap and body imprinted with “FL 1.5” - 3 mg capsules: Green to blue-green cap and white body imprinted with “FL 3” - 4.5 mg capsules: Green to blue-green cap and body imprinted with “FL 4.5” - 6 mg capsules: Purple cap and white body imprinted with “FL 6” ## Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Protect 3 mg and 4.5 mg capsules from light to prevent potential color fading. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Physicians are advised to discuss with patients for whom they prescribe Cariprazine all relevant safety information including, but not limited to, the following: - Dosage and Administration Advise patients that Cariprazine can be taken with or without food. Counsel them on the importance of following dosage escalation instructions. - Neuroleptic Malignant Syndrome (NMS) Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. - Tardive Dyskinesia Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur. - Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight. - Leukopenia/Neutropenia Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking Cariprazine. - Orthostatic Hypotension Counsel patients on the risk of orthostatic hypotension and syncope, especially early in treatment, and also at times of re-initiating treatment or increases in dose. - Interference with Cognitive and Motor Performance Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that Cariprazine therapy does not affect them adversely. - Heat Exposure and Dehydration Educate patients regarding appropriate care in avoiding overheating and dehydration. - Concomitant Medications Advise patients to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs since there is a potential for interactions. - Pregnancy Advise patients that third trimester use of Cariprazine may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with a known or suspected pregnancy. - Pregnancy Registry: Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Cariprazine during pregnancy. # Precautions with Alcohol Alcohol-Cariprazine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names VRAYLAR™ # Look-Alike Drug Names There is limited information regarding Cariprazine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Cariprazine
01dae373d453d5439451a0934508e81c0af5716f	wikidoc	Karl Koller	Karl Koller Karl Koller (born December 3, 1857 in Schüttenhofen, Bohemia (now Susice, Czech Republic) died March 21, 1944 in New York, New York.) was an Austrian ophthalmologist who began his medical career as a surgeon at the Vienna General Hospital, and was a colleague of Sigmund Freud. Koller introduced cocaine as a local anaesthetic for eye surgery. Prior to this discovery, he had tested solutions such as chloral hydrate and morphine as anaesthetics in the eyes of laboratory animals without success. Freud was fully aware of the pain-killing properties of cocaine, but Koller recognized its tissue-numbing capabilities, and in 1884 demonstrated its potential as a local anaesthetic to the medical community. Koller's findings were a medical breakthrough. Prior to his discovery, performing eye surgery was difficult because the involuntary reflex motions of the eye to respond to the slightest stimuli. Later, cocaine was also used as a local anaesthetic in other medical fields such as dentistry. In the 20th century, other agents such as Xylocaine have replaced cocaine as a local anaesthetic. In 1888, Karl Kohler moved to the United States and practiced ophthalmology in New York. He received many distinctions in his career, including being honored by the American Ophthalmological Society as the first recipient of the "Lucien Howe Medal" in 1922. This award is given to physicians in recognition of outstanding achievements in ophthalmology. In 1930 he was also honored by the Medical Association of Vienna. One of Koller's patients was a blind ten-year-old boy named Chauncey Leake. Leake recovered his sight and later discovered the anaesthetic divinyl ether. Koller was reputedly nicknamed "Coca Koller" for his association with the drug and although he was implored to recognise his status as a public figure due to his discovery of local anaesthesia, he did not engage in autobiography.	Karl Koller Karl Koller (born December 3, 1857 in Schüttenhofen, Bohemia (now Susice, Czech Republic) died March 21, 1944 in New York, New York.) was an Austrian ophthalmologist who began his medical career as a surgeon at the Vienna General Hospital, and was a colleague of Sigmund Freud. Koller introduced cocaine as a local anaesthetic for eye surgery. Prior to this discovery, he had tested solutions such as chloral hydrate and morphine as anaesthetics in the eyes of laboratory animals without success. Freud was fully aware of the pain-killing properties of cocaine, but Koller recognized its tissue-numbing capabilities, and in 1884 demonstrated its potential as a local anaesthetic to the medical community. Koller's findings were a medical breakthrough. Prior to his discovery, performing eye surgery was difficult because the involuntary reflex motions of the eye to respond to the slightest stimuli. Later, cocaine was also used as a local anaesthetic in other medical fields such as dentistry. In the 20th century, other agents such as Xylocaine have replaced cocaine as a local anaesthetic. In 1888, Karl Kohler moved to the United States and practiced ophthalmology in New York. He received many distinctions in his career, including being honored by the American Ophthalmological Society as the first recipient of the "Lucien Howe Medal" in 1922. This award is given to physicians in recognition of outstanding achievements in ophthalmology. In 1930 he was also honored by the Medical Association of Vienna. One of Koller's patients was a blind ten-year-old boy named Chauncey Leake. Leake recovered his sight and later discovered the anaesthetic divinyl ether. Koller was reputedly nicknamed "Coca Koller" for his association with the drug and although he was implored to recognise his status as a public figure due to his discovery of local anaesthesia, he did not engage in autobiography. # External links - Koller and Cocaine - Was Dr. Carl Koller driven from Vienna in 1885? "Victory Over Pain-A History of Anaesthesia" by Victor Robinson p246-256 Template:WH Template:WS	https://www.wikidoc.org/index.php/Carl_Koller
ff6bc7eb5e9cc9730b7f11776242859fbbc113bc	wikidoc	Carotidynia	Carotidynia # Overview Carotidynia is a syndrome characterized by unilateral (one-sided) soreness of the carotid artery, near the bifurcation. # Historical Perspective It was first described in 1927 by Temple Fay. The most common cause of carotidynia may be migraine, and then it is usually self-correcting. # Pathophysiology Recent histological evidence has implicated an inflammatory component of carotidynia, but studies are limited. Carotid arteritis is a much less common cause of carotidynia, but has much more serious consequences. It is a form of giant cell arteritis, which is a condition that usually affects arteries in the head. Due to this serious condition possibly causing carotidynia, and the possibility that neck pain is related to some other non-carotidynia and serious condition, the case should be investigated by a medical doctor. # Diagnosis ## MRI MRI and ultrasound studies may be useful in determining the underlying cause of carotidynia. # Treatment Common migraine treatments may help alleviate the carotidynia symptoms.	Carotidynia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Carotidynia is a syndrome characterized by unilateral (one-sided) soreness of the carotid artery, near the bifurcation. # Historical Perspective It was first described in 1927 by Temple Fay[1]. The most common cause of carotidynia may be migraine, and then it is usually self-correcting. # Pathophysiology Recent histological evidence has implicated an inflammatory component of carotidynia, but studies are limited. [2] Carotid arteritis is a much less common cause of carotidynia, but has much more serious consequences. It is a form of giant cell arteritis, which is a condition that usually affects arteries in the head. Due to this serious condition possibly causing carotidynia, and the possibility that neck pain is related to some other non-carotidynia and serious condition, the case should be investigated by a medical doctor.[3] # Diagnosis ## MRI MRI and ultrasound studies may be useful in determining the underlying cause of carotidynia.[4] # Treatment Common migraine treatments may help alleviate the carotidynia symptoms.	https://www.wikidoc.org/index.php/Carotidynia

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